Nitrogen containing heteroaromatics with ortho-substituted P1&#39;s as factor Xa inhibitors

ABSTRACT

The present application describes nitrogen containing heteroaromatics with ortho-substituted P1&#39;s and derivatives thereof of formula I:                    
     or pharmaceutically acceptable salt or prodrug forms thereof, wherein J is N or NH and D is substituted ortho to G on E and may be CH 2 NH 2 , which are useful as inhibitors of factor Xa.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 09/217,336, filed Dec. 21, 1998, now U.S. Pat. No. 5,271,237, which claims the benefit of U.S. Provisional Application Ser. No. 60/068,491, filed Dec. 22, 1997 and U.S. Provisional Application Ser. No. 60/101,075, filed Sep. 18, 1998.

FIELD OF THE INVENTION

This invention relates generally to nitrogen containing heteroaromatics, with ortho-substituted P1 groups, which are inhibitors of trypsin-like serine protease enzymes, especially factor Xa, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.

BACKGROUND OF THE INVENTION

WO 95/18111 addresses fibrinogen receptor antagonists, containing basic and acidic termini, of the formula:

wherein R¹ represents the basic termini, U is an alkylene or heteroatom linker, V may be a heterocycle, and the right hand portion of the molecule represents the acidic termini. The presently claimed compounds do not contain the acidic termini of WO 95/18111.

In U.S. Pat. No. 5,463,071, Himmelsbach et al depict cell aggregation inhibitors which are 5-membered heterocycles of the formula:

wherein the heterocycle may be aromatic and groups A—B—C— and F—E—D— are attached to the ring system. A—B—C— can be a wide variety of substituents including a basic group attached to an aromatic ring. The F—E—D— group, however, would appear to be an acidic functionality which differs from the present invention. Furthermore, use of these compounds as inhibitors of factor Xa is not discussed.

Baker et al, in U.S. Pat. No. 5,317,103, discuss 5-HT₁ agonists which are indole substituted five-membered heteroaromatic compounds of the formula:

wherein R¹ may be pyrrolidine or piperidine and A may be a basic group including amino and amidino. Baker et al, however, do not indicate that A can be a substituted ring system like that contained in the presently claimed heteroaromatics.

Baker et al, in WO 94/02477, discuss 5-HT₁ agonists which are imidazoles, triazoles, or tetrazoles of the formula:

wherein R¹ represents a nitrogen containing ring system or a nitrogen substituted cyclobutane, and A may be a basic group including amino and amidino. Baker et al, however, do not indicate that A can be a substituted ring system like that contained in the presently claimed heteroaromatics.

Illig et al, in WO 97/47299, illustrate amidino and guanidino heterocycle protease inhibitors of the formula:

R¹—Z—X—Y—W

wherein R¹ can be a substituted aryl group, Z is a two carbon linker containing at least one heteroatome, X is a heterocycle, Y is an optional linker and W is an amidino or guanidino containing group. Compounds of this sort are not considered part of the present invention.

Jackson et al, in WO 97/32583, describe cytokine inhibitors useful for inhibiting angiogenesis. These inhibitors include imidazoles of the formula:

wherein R₁ is a variety of heteroaryl groups, R₄ is phenyl, naphthyl, or a heteroaryl group, and R₂ can be a wide variety of groups. Jackson et al do not teach inhibition of factor Xa. Furthermore, the imidazoles of Jackson et al are not considered part of the present invention.

Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca²⁺ and phospholipid). Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation. Thromb. Res. 1979, 15, 617-629), inhibition of factor Xa may be more efficient than inactivation of thrombin in interrupting the blood coagulation system.

Therefore, efficacious and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa inhibitors.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide novel nitrogen containing aromatic heterocycles, with ortho-substituted P1 groups, which are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof.

It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formula (I):

or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, D, E, G, J, M, R^(1a), R^(1b), and s are defined below, are effective factor Xa inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[1] Thus, in a first embodiment, the present invention provides novel compounds of formula I:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein;

ring M contains, in addition to J, 0-3 N atoms, provided that if M contains 2 N atoms then R^(1b) is not present and if M contains 3 N atoms then R^(1a) and R^(1b) are not present;

J is N or NH;

D is selected from CN, C(═NR⁸)NR⁷R⁹, NHC(═NR⁸)NR⁷R⁹, NR⁸CH (═NR⁷), C(O)NR⁷R⁸, and (CR⁸R⁹)_(t)NR⁷R⁸, provided that D is substituted ortho to G on E;

E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, and piperidinyl substituted with 1-2 R;

R is selected from H, Cl, F, Br, I, (CH₂)_(t)OR³, C₁₋₄ alkyl, OCF₃, CF₃, C(O)NR⁷R⁸, and (CR⁸R⁹)_(t)NR⁷R⁸;

G is absent or is selected from NHCH₂, OCH₂, and SCH₂, provided that when s is 0, then G is attached to a carbon atom on ring M;

Z is selected from a C₁₋₄ alkylene, (CH₂)_(r)O(CH2)_(r), (CH₂)_(r)NR³(CH₂)_(r), (CH₂)_(r)C(O)(CH₂)_(r), (CH₂)_(r), C(O)O(CH₂)_(r), (CH₂)_(r)OC(O)(CH₂)_(r), (CH₂)_(r)C(O)NR³(CH₂)_(r), (CH₂)_(r)NR³C(O)(CH₂)_(r), (CH₂)_(r)OC(O)O(CH₂)_(r), (CH₂)_(r)OC(O)NR³(CH₂)_(r), (CH₂)_(r)NR³C(O)O(CH₂)_(r), (CH₂)_(r)NR³C(O)NR³(CH₂)_(r), (CH₂)_(r)S(O)_(p)(CH₂)_(r), (CH₂)_(r)SO₂NR³(CH₂)_(r), (CH₂)_(r)NR³SO₂(CH₂)_(r), and (CH₂)_(r)NR³SO₂NR³(CH₂)_(r), provided that Z does not form a N—N, N—O, N—S, NCH₂N, NCH₂O, or NCH₂S bond with ring M or group A;

R^(1a) and R^(1b) are independently absent or selected from —(CH₂)_(r)—R^(1′), —CH═CH—R^(1′), NCH₂R^(1″), OCH₂R^(1″), SCH₂R^(1″), NH(CH₂)₂(CH₂)_(t)R^(1′), O(CH₂)₂(CH₂)_(t)R^(1′), and S(CH₂)₂(CH₂)_(t)R^(1′);

alternatively, R^(1a) and R^(1b) , when attached to adjacent carbon atoms, together with the atoms to which they are attached form a 5-8 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R⁴ and which contains from 0-2 heteroatoms selected from the group consisting of N, O, and S;

R^(1′) is selected from H, C₁₋₃ alkyl, F, Cl, Br, I, —CN, —CHO, (CF₂)_(r)CF₃, (CH₂)_(r)OR², NR²R^(2a), C(O)R^(2c), OC(O) R², (CF₂)_(r)CO₂R^(2c), S(O)_(p)R^(2b), NR²(CH₂)_(r)OR², CH(═NR^(2c))NR²R^(2a), NR²C(O)R^(2b), NR²C(O)NHR^(2b), NR²C(O)₂R^(2a), OC(O)NR^(2a)R^(2b), C(O)NR²R^(2a), C(O)NR²(CH₂)_(r)OR², SO₂NR²R^(2a), NR²SO₂R², C₃₋₆ carbocyclic residue substituted with 0-2 R⁴, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁴;

R^(1″) is selected from H, CH(CH₂OR²)₂, C(O)R^(2c), C(O)NR²R^(2a), S(O)R^(2b), S(O)₂R^(2b), and SO₂NR²R^(2a);

R², at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b);

R^(2a), at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b);

R^(2b), at each occurrence, is selected from CF₃, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b);

R^(2c), at each occurrence, is selected from CF₃, OH, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b);

alternatively, R² and R^(2a) combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R^(4b) which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

alternatively, R² and R^(2a), together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R^(4b) and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

R^(3a), at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

R^(3b), at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

R^(3c), at each occurrence, is selected from C₁₋₄ alkyl, and phenyl;

A is selected from:

C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁴, and

5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁴;

B is selected from:

X—Y NR²R^(2a), C(═NR²)NR²R^(2a), NR²C(═NR²)NR²R^(2a),

C₃₋₁₀ carbocyclic residue substituted with 0-2 R^(4a), and

5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4a);

X is selected from C₁₋₄ alkylene, —CR²(CR²R^(2b))(CH₂)_(t)—, —C(O)—, —C(═NR¹)—, —CR²(NR^(1′)R²)—, —CR²(OR²)—, —CR²(SR²)—, —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —S(O)_(p)—, —S(O)_(p)CR²R^(2a)—, —CR²R^(2a)S (O)_(p)—, —S(O)₂NR²—, —NR²S(O)₂—, —NR²S (O)₂CR²R^(2a)—, —CR²R^(2a)S(O)₂NR²—, —NR²S(O)₂NR²—, —C(O)NR²—, —NR²C(O)—, —C(O)NR²CR²R^(2a)—, —NR²C(O)CR²R^(2a)—, —CR²R^(2a)C(O)NR²—, —CR²R^(2a)NR²C(O)—, —NR²C(O)O—, —OC(O)NR²—, —NR²C(O)NR²—, —NR²—, NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O, —CR²R^(2a)O—, and —OCR²R^(2a)—;

Y is selected from:

(CH₂)_(r)NR²R^(2a), provided that X—Y do not form a N—N, O—N, or S—N bond,

C₃₋₁₀ carbocyclic residue substituted with 0-2 R^(4a), and

5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4a);

R⁴, at each occurrence, is selected from H, ═O, (CH₂)_(r)OR², F, Cl, Br, I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R²C, NR²C(O)R^(2b), C(O)NR²R^(2a), NR²C(O)NR²R^(2a), CH(═NR²)NR²R^(2a), CH(═NS(O)₂R⁵)NR²R^(2a), NHC(═NR²)NR²R^(2a), C(O)NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, (CF₂)_(r)CF₃, NCH₂R^(1″), OCH₂R^(1″), SCH₂R^(1″), N(CH₂)₂(CH₂)_(t)R_(1′), O(CH₂)₂(CH₂)_(t)R^(1′), and S(CH₂)₂(CH₂)_(t)R¹′,

alternatively, one R⁴ is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

R^(4a), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR², (CH₂)_(r)—F, (CH₂)_(r)—Br, (CH₂)_(r)—Cl, Cl, Br, F, I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), NR²C(O)R^(2b), C(O)NR²R^(2a), C(O)NH(CH₂)₂NR²R^(2a), NR²C(O)NR²R^(2a), CH(═NR²)NR²R^(2a), NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, C(O)NHSO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, and (CF₂)_(r)CF₃;

alternatively, one R^(4a) is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R⁵;

R^(4b), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR³, F, Cl, Br, I, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³, (CH₂)_(r)C(O)OR^(3c), NR³C(O)R^(3a), C(O)NR³R^(3a), NR³C(O)NR³R^(3a), CH(═NR³)NR³R^(3a), NR³C(═NR³)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl, NR³SO₂CF₃, NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)—C₁₋₄ alkyl, S(O)_(p)-phenyl, and (CF₂)_(r)CF₃;

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl substituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶;

R⁶, at each occurrence, is selected from H, OH, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r)NR²R^(2a),(CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), NR²C(O)NR²R^(2a), CH(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂NR²R^(2a), and NR²SO₂C₁₋₄ alkyl;

R⁷, at each occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, (CH₂)_(n)-phenyl, C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl;

R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl and (CH₂)_(n)-phenyl;

alternatively, R⁷ and R⁸ combine to form a 5 or 6 membered saturated, ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl and (CH₂)_(n)-phenyl;

n, at each occurrence, is selected from 0, 1, 2, and 3;

m, at each occurrence, is selected from 0, 1, and 2;

p, at each occurrence, is selected from 0, 1, and 2;

r, at each occurrence, is selected from 0, 1, 2, and 3;

s, at each occurrence, is selected from 0, 1, and 2; and,

t, at each occurrence, is selected from 0, 1, 2, and 3;

provided that D—E—G—(CH₂)_(s)— and —Z—A—B are not both benzamidines.

[2] In a preferred embodiment, the present invention provides novel compounds of formulae Ia-Ih:

wherein, groups D—E— and —Z—A—B are attached to adjacent atoms on the ring;

R is selected from H, Cl, F, Br, I, (CH₂)_(t)OR³, C₁₋₄ alkyl, OCF₃, CF₃, C(O)NR⁷R⁸, and (CR⁸R⁹)_(t)NR⁷R⁸;

Z is selected from a CH₂O, OCH₂, CH₂NH, NHCH₂, C(O), CH₂C(O), C(O)CH₂, NHC(O), C(O)NH, CH₂S(O)₂, S(O)₂(CH₂), SO₂NH, and NHSO₂, provided that Z does not form a N—N, N—O, NCH₂N, or NCH₂O bond with ring M or group A;

A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R⁴;

phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;

B is selected from: Y, X—Y, NR²R^(2a), C(═NR²)NR²R^(2a), and NR²C(═NR²) NR²R^(2a);

X is selected from C₁₋₄ alkylene, —C(O)—, —C(═NR)—, —CR²(NR²R^(2a))—, —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —C(O)NR²—, —NR²C(O)—, —C(O)NR²CR²R^(2a)—, —NR²C(O)CR²R^(2a)—, —CR²R^(2a)C(O)NR²—, —CR²R^(2a)NR²C(O)—, —NR²C(O)NR₂—, —NR²—, —NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O, —CR²R^(2a)O—, and —OCR²R^(2a)—;

Y is NR²R^(2a), provided that X—Y do not form a N—N or O—N bond;

alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R^(4a);

cylcopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;

alternatively, Y is selected from the following bicyclic heteroaryl ring systems:

K is selected from O, S, NH, and N.

[3] In a more preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf:

wherein;

Z is selected from a C(O), CH₂C(O), C(O)CH₂, NHC(O), C(O)NH, C(O)N(CH₃) , CH₂S(O)₂, S(O)₂(CH₂), SO₂NH, and NHSO₂, provided that Z does not form a N—N or NCH₂N bond with ring M or group A.

[4] In an even more preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;

E is phenyl substituted with R or 2-pyridyl substituted with R;

D is selected from NH₂, NHCH₃, CH₂NH₂, CH₂NHCH₃, CH(CH₃)NH₂, and C(CH₃)₂NH₂, provided that D is substituted ortho to ring M on E; and,

R is selected from H, OCH₃, Cl, and F.

[5] In a further preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;

D—E is selected from 2-aminophenyl, 2-methylaminophenyl, 2-aminomethylphenyl, 4-methoxy-2-aminophenyl, 4-methoxy-2-(methylamino)phenyl, 4-methoxy-2-aminomethylphenyl, 4-methoxy-2-(methylaminomethyl)phenyl, 4-methoxy-2-(1-aminoethyl)phenyl, 4-methoxy-2-(2-amino-2-propyl)phenyl, 4-Cl-2-aminophenyl, 4-Cl-2-(methylamino)phenyl, 4-Cl-2-aminomethylphenyl, 4-Cl-2-(methylaminomethyl)phenyl, 4-Cl-2-(1-aminoethyl)phenyl, 4-Cl-2-(2-amino-2-propyl)phenyl, 4-F-2-aminophenyl, 4-F-2-(methylamino)phenyl, 4-F-2-aminomethylphenyl, 4-F-2-(methylaminomethyl)phenyl, 4-F-2-(1-aminoethyl)phenyl, and 4-F-2-(2-amino-2-propyl)phenyl.

[6] In another even more preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;

Z is C(O)CH₂ and CONH, provided that Z does not form a N—N bond with group A;

A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R⁴; and,

B is selected from X—Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R^(4a);

R⁴, at each occurrence, is selected from OH, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), and (CF₂)_(r)CF₃;

R^(4a) is selected from C₁₋₄ alkyl, CF₃, S(O)_(p)R⁵, SO₂NR²R^(2a), and 1-CF₃-tetrazol-2-yl;

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, and benzyl;

X is CH₂ or C(O); and,

Y is selected from pyrrolidino and morpholino.

[7] In another further preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;

A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and,

B is selected from the group: 2-CF3-phenyl, 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 4-morpholino, 2-(1′-CF₃-tetrazol-2-yl)phenyl, 4-morpholinocarbonyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl, 2-methylsulfonyl-1-imidazolyl and, 5-methyl-1,2,3-triazolyl.

[8] In another even more preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;

E is phenyl substituted with R or 2-pyridyl substituted with R;

D is selected from NH_(2,) NHCH₃, CH₂NH₂, CH₂NHCH₃, CH(CH₃)NH₂, and C(CH₃)₂NH₂, provided that D is substituted ortho to ring M on E; and,

R is selected from H, OCH₃, Cl, and F;

Z is C(O)CH₂ and CONH, provided that Z does not form a N—N bond with group A;

A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R⁴; and,

B is selected from X—Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R^(4a);

R⁴, at each occurrence, is selected from OH, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), and (CF₂)_(r)CF₃;

R^(4a) is selected from C₁₋₄ alkyl, CF₃, S(O)_(p)R⁵, SO₂NR²R^(2a), and 1-CF₃-tetrazol-2-yl;

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, and benzyl;

X is CH₂ or C(O); and,

Y is selected from pyrrolidino and morpholino.

[9] In another further preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;

D—E is selected from 2-aminophenyl, 2-methylaminophenyl, 2-aminomethylphenyl, 4-methoxy-2-aminophenyl, 4-methoxy-2-(methylamino)phenyl, 4-methoxy-2-aminomethylphenyl, 4-methoxy-2-(methylaminomethyl)phenyl, 4-methoxy-2-(1-aminoethyl)phenyl, 4-methoxy-2-(2-amino-2-propyl)phenyl, 4-Cl-2-aminophenyl, 4-Cl-2-(methylamino)phenyl, 4-Cl-2-aminomethylphenyl, 4-Cl-2-(methylaminomethyl)phenyl, 4-Cl-2-(1-aminoethyl)phenyl, 4-Cl-2-(2-amino-2-propyl)phenyl, 4-F-2-aminophenyl, 4-F-2-(methylamino)phenyl, 4-F-2-aminomethylphenyl, 4-F-2-(methylaminomethyl)phenyl, 4-F-2-(1-aminoethyl)phenyl, and 4-F-2-(2-amino-2-propyl)phenyl;

A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and,

B is selected from the group: 2-CF₃-phenyl, 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 4-morpholino, 2-(1′-CF₃-tetrazol-2-yl)phenyl, 4-morpholinocarbonyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl, 2-methylsulfonyl-1-imidazolyl and, 5-methyl-1,2,3-triazolyl.

[10] In a still further preferred embodiment, the present invention provides a novel compound of formula IIa.

[11] In another still further preferred embodiment, the present invention provides a novel compound of formula IIb.

[12] In another still further preferred embodiment, the present invention provides a novel compound of formula IIc.

[13] In another still further preferred embodiment, the present invention provides a novel compound of formula IId.

[14] In another still further preferred embodiment, the present invention provides a novel compound of formula IIe.

[15] In another still further preferred embodiment, the present invention provides a novel compound of formula IIf.

[16] In another even more preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;

D is selected from —CN, C(═NR⁸)NR⁷R⁹, C(O)NR⁷R⁸, NR⁷R⁸, and CH₂NR⁷R⁸, provided that D is substituted ortho to ring M on E;

E is phenyl substituted with R or pyridyl substituted with R;

R is selected from H, Cl, F, OR³, CH₃, CH₂CH₃, OCF₃, CF₃, NR⁷R⁸, and CH₂NR⁷R⁸;

Z is selected from C(O), CH₂C(O), C(O)CH₂, NHC(O), and C(O)NH, provided that Z does not form a N—N bond with ring M or group A;

R^(1a) and R^(1b) are independently absent or selected from —(CH₂)_(r)—R^(1′), NCH₂R^(1″), OCH₂R¹−, SCH₂R^(1″), N(CH₂)₂(CH₂)_(t)R^(′), O(CH₂)₂(CH₂)_(t)R^(1′), and S(CH₂)₂(CH₂)_(t)R^(1′), or combined to form a 5-8 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R⁴ and which contains from 0-2 heteroatoms selected from the group consisting of N, O, and S;

R¹′, at each occurrence, is selected from H, C₁₋₃ alkyl, halo, (CF₂)_(r)CF_(3,) OR², NR²R^(2a), C(O)R^(2c), (CF₂)_(r)CO₂R^(2c), S(O)_(p)R^(2b), NR²(CH₂)_(r)OR², NR²C(O)R^(2b), NR²C(O)₂R^(2b), C(O)NR²R^(2a), SO₂NR²R^(2a), and NR²SO₂R^(2b);

A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R⁴;

phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl;

B is selected from: Y, X—Y, NR²R^(2a), C(═NR²)NR²R^(2a), and NR²C(═NR²)NR²R^(2a);

X is selected from CH₂, —CR²(CR²R^(2b)) (CH₂)_(t)—, —C(O)—, —C(═NR)—, —CH(NR²R^(2a))—, —C(O)NR²—, —NR²C(O)—, —NR²C(O)NR²—, —NR²—, and O;

Y is NR²R^(2a), provided that X—Y do not form a N—N or O—N bond; alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R^(4a);

phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl;

R⁴, at each occurrence, is selected from ═O, OH, Cl, F, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), C(O)NR²R^(2a), CH(═NH)NH₂, NHC (+NH) NH₂, SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, and (CF₂)_(r)CF₃;

R^(4a), at each occurrence, is selected from ═O, OH, Cl, F, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), C(O)NR²R^(2a), CH(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, (CF2)_(r)CF3, and 1-CF₃-tetrazol-2-yl;

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl substituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶;

R⁶, at each occurrence, is selected from H, ═O, OH, OR², Cl, F, CH₃, CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), CH(═NH) NH₂, NHC (═NH) NH₂, and SO₂NR²R^(2a);

R⁷, at each occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, benzyl, C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl;

R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl and benzyl; and

alternatively, R⁷ and R⁸ combine to form a morpholino group; and,

R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl and benzyl.

[17] In a another further preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;

E is phenyl substituted with R or 2-pyridyl substituted with R;

R is s elected from H, Cl, F, OCH₃, CH₃, OCF₃, CF₃, NH₂, and CH₂NH₂;

Z is selected from a C(O)CH₂ and C(O)NH, provided that Z does not form a N—N bond with group A;

R^(1a) is selected from H, CH₃, CH₂CH₃, Cl, F, CF₃, OCH₃, NR²R^(2a), S(O)_(p)R^(2b), CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2c), CH₂C(O)R^(2c), C(O)NR²R^(2a), and SO₂NR²R^(2a);

R^(1b) is selected from H, CH₃, CH₂CH₃, Cl, F, CF₃, OCH₃, NR²R^(2a), S(O)_(p)R^(2b), CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2c), CH₂C(O)R^(2c), C(O)NR²R^(2a), and SO₂NR²R^(2a);

A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R⁴;

phenyl, pyridyl, pyrimidyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl;

B is selected from: Y and X—Y ;

X is selected from CH₂, —CR²(CR²R^(2b))—, —C(O)—, —C(═NR)—, —CH(NR²R^(2a))—, —C(O)NR²—, —NR²C(O)—, —NR²C(O)NR²—, —NR²—, and O;

Y is NR²R^(2a), provided that X—Y do not form a N—N or O—N bond;

alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R^(4a);

phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl;

R², at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl;

R^(2a), at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl;

R^(2b), at each occurrence, is selected from CF₃, OCH₃, CH₃, benzyl, and phenyl;

R^(2c), at each occurrence, is selected from CF₃, OH, OCH₃, CH₃, benzyl, and phenyl;

alternatively, R² and R^(2a)combine to form a 5 or 6 membered saturated, partially unsaturated, or unsaturated ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

R³, at each occurrence, is selected from H, CH₃, CH₂CH₃, and phenyl;

R^(3a), at each occurrence, is selected from H, CH₃, CH₂CH₃, and phenyl;

R⁴, at each occurrence, is selected from OH, Cl, F, CH₃, CH₂CH₃, NR²R^(2a), Ch₂NR²R^(2a), C(O)R^(2b), NR²C(O)NR^(2b), C(O)NR²R^(2a), and CF₃;

R^(4a), at each occurrence, is selected from OH, Cl, F, CH₃, CH₂CH₃, NR²R^(2a), CH₂NR²R^(2a), C(O)R^(2b), C(O)NR²R^(2a), SO₂NR²R^(2a), S(O)_(p)R⁵, CF₃, and 1-CF₃-tetrazol-2-yl;

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl substituted with 0-2 R⁶, and benzyl substituted with 1 R⁶;

R⁶, at each occurrence, is selected from H, OH, OCH₃, Cl, F, CH₃, CN, NO₂, NR²R^(2a), CH₂NR²R^(2a), and SO₂NR²R^(2a);

R⁷, at each occurrence, is selected from H and C₁₋₃ alkyl;

R⁸, at each occurrence, is selected from H, CH₃, and benzyl;

R⁹, at each occurrence, is selected from H, CH₃, and benzyl; and,

t, at each occurrence, is selected from 0 and 1.

[18] In a another still further preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;

D is selected from NR⁷R⁸, and CH₂NR⁷R⁸, provided that D is substituted ortho to ring M on E;

R^(1a) is absent or is selected from H, CH₃, CH₂CH₃, Cl, F, CF₃, OCH₃, NR²R^(2a), S(O)_(p)R^(2b), C(O)NR²R^(2a), CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2c), CH₂C(O)R^(2c), and SO₂NR²R^(2a);

R^(1b) is absent or is selected from H, CH₃, CH₂CH₃, Cl, F, CF₃, OCH₃, NR²R^(2a), S(O)_(p)R^(2b), C(O)NR²R^(2a), CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2b), CH₂C(O)R^(2b), and SO₂NR²R^(2a);

A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R⁴; phenyl, pyridyl, and pyrimidyl;

B is selected from: Y and X—Y ;

X is selected from —C(O)— and O;

Y is NR²R^(2a), provided that X—Y do not form a O—N bond;

alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R^(4a);

phenyl, piperazinyl, pyridyl, pyrimidyl, morpholinyl, pyrrolidinyl, imidazolyl, and 1,2,3-triazolyl;

R², at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl;

R^(2a), at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl;

R^(2b), at each occurrence, is selected from CF₃, OCH₃, CH₃, benzyl, and phenyl;

R^(2c), at each occurrence, is selected from CF₃, OH, OCH₃, CH₃, benzyl, and phenyl;

alternatively, R² and R^(2a) combine to form a ring system selected from pyrrolidinyl, piperazinyl and morpholino;

R⁴, at each occurrence, is selected from Cl, F, CH₃, NR²R^(2a), and CF₃;

R^(4a), at each occurrence, is selected from Cl, F, CH₃, SO₂NR²R^(2a), S(O)_(p)R⁵, and CF₃;

R⁵, at each occurrence, is selected from CF₃ and CH₃;

R⁷, at each occurrence, is selected from H, CH₃, and CH₂CH₃; and,

R⁸, at each occurrence, is selected from H and CH₃.

[19] Specifically preferred compounds of the present invention are selected from the group:

3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-sulfamido-[1,1′]-biphen-4-yl))carboxyamide;

3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-sulfamido-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-sulfamido-[1,1′]-biphen-4-yl))carboxyamide;

3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-sulfamido-[1,1′]-biphen-4-yl))carboxyamide;

3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-sulfamido-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-sulfamido-[1,1′]-biphen-4-yl))carboxyamide;

3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-sulfamido-[1,1′]-biphen-4-yl))carboxyamide;

3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-sulfamido-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-sulfamido-[1,1′]-biphen-4-yl))carboxyamide;

3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-sulfamido-[1,1′]-biphen-4-yl))carboxyamide;

3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-sulfamido-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-sulfamido-[1,1′]-biphen-4-yl))carboxyamide;

3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-(1-pyrrolidinocarbonyl)phenyl)carboxyamide;

3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-(1-pyrrolidinocarbonyl)phenyl)carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-(1-pyrrolidinocarbonyl)phenyl)carboxyamide;

3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-(1- pyrrolidinocarbonyl)phenyl)carboxyamide;

3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-(1-pyrrolidinocarbonyl)phenyl)carboxyamide;

3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-(1-pyrrolidinocarbonyl)phenyl)carboxyamide;

3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-(1-pyrrolidinocarbonyl)phenyl)carboxyamide;

3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-(1-pyrrolidinocarbonyl)phenyl)carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-(1-pyrrolidinocarbonyl)phenyl)carboxyamide;

3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-(1-pyrrolidinocarbonyl)phenyl)carboxyamide;

3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-(1-pyrrolidinocarbonyl)carboxyamide;

3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-(1-pyrrolidinocarbonyl)phenyl)carboxyamide;

3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-sulfamido)phenyl)pyridin-2-yl)carboxyamide;

3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-sulfamido)phenyl)pyridin-2-yl)carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-sulfamido)phenyl)pyridin-2-yl)carboxyamide;

3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-sulfamido)phenyl)pyridin-2-yl)carboxyamide;

3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-sulfamido)phenyl)pyridin-2-yl)carboxyamide;

3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-sulfamido)phenyl)pyridin-2-yl) carboxyamide;

3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-methylsulphonyl)phenyl)pyridin-2-yl)carboxyamide;

3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-(2-methylsulphonyl)phenyl)pyridin-2-yl)carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-methylsulphonyl)phenyl)pyridin-2-yl)carboxyamide;

3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-methylsulphonyl)phenyl)pyridin-2-yl)carboxyamide;

3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-methylsulphonyl)phenyl)pyridin-2-yl)carboxyamide;

3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-methylsulphonyl)phenyl)pyridin-2-yl)carboxyamide;

3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-sulfamido)phenyl)pyrimidin-2-yl)carboxyamide;

3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-sulfamido)phenyl)pyrimidin-2-yl)carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-sulfamido)phenyl)pyrimidin-2-yl)carboxyamide;

3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-sulfamido)phenyl)pyrimidin-2-yl)carboxyamide;

3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-sulfamido)phenyl)pyrimidin-2-yl)carboxyamide;

3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-sulfamido)phenyl)pyrimidin-2-yl)carboxyamide;

3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-methylsulphonyl)phenyl)pyrimidin-2-yl)carboxyamide;

3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-(2-methylsulphonyl)phenyl)pyrimidin-2-yl)carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-methylsulphonyl)phenyl)pyrimidin-2-yl)carboxyamide;

3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-methylsulphonyl)phenyl)pyrimidin-2-yl)carboxyamide;

3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-methylsulphonyl)phenyl)pyrimidin-2-yl)carboxyamide;

3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-((2-methylsulphonyl)phenyl)pyrimidin-2-yl)carboxyamide;

3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-((2-methyl) imidazo-1-yl)phenyl) carboxyamide;

3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-((2-methyl) imidazo-1-yl) phenyl) carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-((2-methyl) imidazo-1-yl)phenyl)carboxyamide;

3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-((2-methyl) imidazo-1-yl)phenyl)carboxyamide;

3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-((2-methyl)imidazo-1-yl)phenyl)carboxyamide;

3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-((2-methyl)imidazo-1-yl)phenyl)carboxyamide;

3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-((5-methyl)imidazo-1-yl)phenyl)carboxyamide;

3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-((5-methyl)imidazo-1-yl)phenyl)carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-((5-methyl)imidazo-1-yl)phenyl)carboxyamide;

3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-((5-methyl)imidazo-1-yl)phenyl)carboxyamide;

3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-((5-methyl)imidazo-1-yl)phenyl)carboxyamide;

3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-((5-methyl)imidazo-1-yl)phenyl)carboxyamide;

3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-((2-methyl)imidazo-1-yl)phenyl)carboxyamide;

3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-((2-methyl)imidazo-1-yl)phenyl)carboxyamide;

b 3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-((2-methyl)imidazo-1-yl) phenyl)carboxyamide;

3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-((2-methyl)imidazo-1-yl)phenyl)carboxyamide;

3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-((2-methyl)imidazo-1-yl)phenyl)carboxyamide; 3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-((2-methyl)imidazo-1-yl)phenyl)carboxyamide;

3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-((5-methyl)imidazo-1-yl)phenyl)carboxyamide;

3-Ethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-((5-methyl)imidazo-1-yl)phenyl)carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-((5-methyl)imidazo-1-yl)phenyl)carboxyamide;

3-Methyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-((5-methyl)imidazo-1-yl)phenyl)carboxyamide;

3-Ethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-((5-methyl)imidazo-1-yl)phenyl)carboxyamide; and,

3-Trifluoromethyl-1-(2-N-methylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-((5-methyl)imidazo-1-yl)phenyl)carboxyamide;

and pharmaceutically acceptable salts thereof.

[20] More specifically preferred compounds of the present invention are selected from the group:

3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-sulfamido-[1,1′]-biphen-4-yl))carboxyamide;

5-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-3-(N-(2′-sulfamido-[1,1′]-biphen-4-yl))carboxyamide;

3-Methyl-1-(2-N,N-dimethylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-N-methylsulfamido-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-sulfamido-[1,1]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-methylsulfonyl-[1,1-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-sulfamido-[1,1]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-N-pyrrolidinocarbonyl)phenyl)carboxyamide;

N-Benzylsulfonyl-4-(3-trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxyamido)piperidine;

3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-(2′-sulfonamido)phenyl)pyrid-2-yl)carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-(pyrid-2-yl))pyrid-2-yl)carboxyamide;

N-Benzyl-4-(3-trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxyamido)piperidine;

N-Phenylsulfonyl-4-(3-trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxyamido)piperidine;

3-Trifluoromethyl-1-(2-aminomethyl-4-chlorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-(1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4-chlorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2-sulfamido-[1,1]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-5-chlorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4-chlorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2-sulfamido-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4-fluorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4-fluorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2-sulfamido-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-5-fluorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-5-fluorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-sulfamido-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4,5-difluorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4,5-difluorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-sulfamido-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-3-fluorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-3-fluorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-sulfamido-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4-fluorophenyl)-1H-pyrazole-5-(N-(4-(2-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4-fluorophenyl)-1H-pyrazole-5-(N-(4-(2-sulfamido-(1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-aminomethyl-4-fluorophenyl)-1H-pyrazole-5-(N-(4-(N-((N′-methylsulfonyl)iminoly)pyrrolidino))phenyl)carboxyamide;

3-Trifluoromethyl-1-(2-(N-glycyl)aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-(N-phenylacetyl)aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

3-(Trifluoromethyl)-1-(2-(aminomethyl)phenyl)-1H-pyrazole-5-(N-(2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-(aminomethyl)phenyl)-1H-pyrazole-5-(N-(2′-aminosulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-(aminomethyl)phenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-aminosulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-(aminomethyl)phenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-(N-(glycyl)aminomethyl)phenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-((N-(N-methylglycyl)aminomethyl)phenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-carboxamidophenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

3-Trifluoromethyl-1-(2-cyanophenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide;

1-(2′-Aminomethylphenyl)-5-[[(2′-methylsulfonyl)-3-fluoro-[1,1]-biphen-4-yl]aminocarbonyl]-tetrazole;

1-(2′-Aminomethylphenyl)-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]-tetrazole;

1-[2-(Aminomethyl)phenyl]-3-thiomethoxy-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole;

1-[2-(Aminomethyl)phenyl]-3-methylsulfonyl-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole;

1-[2-(Aminomethyl)phenyl]-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]triazole;

1-[2-(Aminomethyl)phenyl]-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole;

1-[2-(Aminomethyl)phenyl]-3-trifluoromethyl-5-[((2-fluoro)-(2′-pyrrolidinomethyl)-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole; and,

1-[2-(Aminomethyl)phenyl]-3-trifluoromethyl-5-[((2-fluoro)-(2′-hydroxymethyl)-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole;

and pharmaceutically acceptable salts thereof.

In a second embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.

In a third embodiment, the present invention provides a novel method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.

Definitions

The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.

The term “substituted,” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties.

The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

When any variable (e.g., R⁶) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R⁶, then said group may optionally be substituted with up to two R⁶ groups and R⁶ at each occurrence is selected independently from the definition of R⁶. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein, “alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. “Haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. “Alkoxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. “Cycloalkyl” is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. Alkenyl” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. “Alkynyl” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, and iodo; and “counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.

As used herein, “carbocycle” or “carbocyclic residue” is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.

As used herein, the term “heterocycle” or “heterocyclic system” is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term “aromatic heterocyclic system” or “heteroaryl” is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

“Prodrugs” are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like. Preferred prodrugs are amidine prodrugs wherein D is C(═NR⁷)NH₂ or its tautomer C(═NH)NHR⁷ and R⁷ is selected from OH, C₁₋₄ alkoxy, C₆₋₁₀ aryloxy, C₁₋₄ alkoxycarbonyl, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, and C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl. More preferred prodrugs are where R⁷ is OH, methoxy, ethoxy, benzyloxycarbonyl, methoxycarbonyl, and methylcarbonyloxymethoxycarbonyl.

“Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

“Substituted” is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O) group, then 2 hydrogens on the atom are replaced.

“Therapeutically effective amount” is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit HIV infection or treat the symptoms of HIV infection in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.

Synthesis

The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups resent in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991). All references cited herein are hereby incorporated in their entirety herein by reference.

The compounds of Formula I in which ring M is pyrrole can be prepared by the procedures described in Schemes 1-9. In Scheme 1 is shown how to prepare pyrroles in which the group Q—E is attached to the pyrrole nitrogen, wherein Q is a functionality that can be converted into D of Formula I, R^(e) is functionality that can be converted into Z—A—B of Formula I and R^(f) is or can be converted into R^(1a) of Formula I. Oxidation of a furan with bromine in acetic acid can afford a 2,5-diacetoxydihydrofuran which can react with amine Q—E—NH2 to afford a pyrrole. Vilsmeier-Haack formylation with phosphorous oxychloride and DMF preferentially can acylate the pyrrole ring at C-2. Oxidation of the resulting aldehyde can give a carboxylic acid. The carboxylic acid can then be converted into amine derivatives using either the Hofmann degradation of the derived primary amide (Huisgen et. al. Chem. Ber. 1960, 93, 65) or the Curtius rearrangement of the derived acyl azide (J. Prakt. Chem. 1909, 42, 477). Derivatives which contain a sulfur atom attached to the pyrrole ring can be obtained by direct sulfonation with pyridine sulfur trioxide complex to give the sulfonic acids or treatment with copper (II) thiocyanate (J. Het. Chem. 1988, 25, 431) followed by the reduction of the intermediate thiocyanate with sodium borohydride to give a mercaptan.

In Scheme 2 is shown how to prepare pyrroles in which Q—E is attached to the 2-position, wherein R^(f) and R^(g) collectively are hydrogen or a group that can be converted into R^(1a) and R^(1b) of Formula I. The Hantzsch pyrrole synthesis is a versatile reaction involving the cyclization of an appropriate β-ketoester with an α-halo ketone or aldehyde in the presence of a primary amine (Ber. Dtsch. Chem. Ges. 1890, 23, 1474). The β-ketoesters can be prepared from acid chlorides (X=Cl) by the addition of the magnesium anion of potassium alkylmalonate followed by decarboxylation (Synthesis 1993, 290). Alternatively, β-ketoesters can be prepared from an appropriate aldehyde (R=H) by Reformatsky reaction with an α-bromoacetate followed by oxidation. Cyclization with an α-halo ketone or aldehyde in the presence of a primary amine can afford pyrroles. Acidic hydrolysis of the 3-carboalkoxy pyrrole can afford the carboxylic acids. Pyrroles which contain a 3-amino substituent can be prepared from the acids by treatment with phosphoryl azide and triethylamine to effect a Curtius rearrangement to afford the isocyanates (J. Med. Chem. 1981, 24, 33) which upon hydrolysis can yield 3-aminopyrroles. Pyrroles which contain a sulfur atom at C-3 can be prepared from the acids by employing the Hunsdiecker procedure to give the 3-bromo derivatives. Halogen-metal exchange at low temperature with an alkyllithium reagent can afford the 3-lithio derivative which can be quenched with a variety of electrophiles, such as S₈ to afford thiols directly or Cu(SCN)₂ to afford a thiocyanate which can be reduced with sodium borohydride. The thiols can further be oxidized to the sulfonic acid derivatives by an oxidant such as KMnO₄.

In Scheme 3 is shown how to prepare pyrroles in which Q—E is attached to the 3-position. This scheme relies upon the extremely versatile Knorr pyrrole synthesis, which involves condensation of a-aminoketones with β-ketoesters. The α-aminoketones can be prepared from β-ketoesters (Scheme 2) by nitrosation followed by reduction with zinc/acetic acid. Condensation of α-aminoketones with appropriate β-ketoesters can afford good yields of pyrroles. These intermediates are very versatile and can be converted into pyrroles with a wide variety of substituents with varying substitution patterns. For cases wherein R^(e) (Z—A—B precursor) is at the 2-position, acidic hydrolysis can selectively hydrolyze the C-3 ester. Heating should then effect decarboxylation. Hydrolysis of the 2-carboxylic acid can be achieved under basic conditions. Curtius rearrangement of the acid as described previously can afford the amino derivatives. To prepare compounds with a sulfur atom attached to C-2, basic hydrolysis and decarboxylation can afford the C-2 unsubstituted pyrroles. These pyrroles can undergo electrophilic substitution to afford thiols (Cu(SCN)₂, then NaBH₄) and sulfonic acids (pyridine SO₃ complex or chlorosulfonic acid). The R^(1a) group contained in Formula I can be derived either from the remaining ester or from R^(f). Alternatively, the thiol and sulfonic acid derivatives can also be derived form the C-2 acids by manipulation of the carboxylic acid group as described previously.

In Scheme 4 is shown how to prepare pyrroles in which Q—E is attached to the 3-position. Cyclization of α-aminoketones as described previously with β-ketoesters can afford pyrroles. Hydrolysis under basic conditions can selectively hydrolyze the C-2 ester which upon heating should undergo decarboxylation to afford 2-unsubstituted pyrroles. The C-3 ester can then be hydrolyzed under acidic conditions to afford the 3-carboxypyrroles. Curtius rearrangement under conditions described previously can afford the 3-aminopyrroles. The carboxylic acids can be used to prepare the 3-mercapto and 3-sulfonic acid derivatives. The Hunsdiecker procedure can be used to prepare the 3-bromopyrroles. Halogen metal exchange with t-BuLi at low temperature followed by quenching with copper isocyanate should introduce an isocyanate group at C-3. This intermediate can be reduced with sodium borohydride to afford the 3-mercaptopyrroles. Alternatively, the carboxylic acids can be decarboxylated to afford pyrroles which can be N-protected with a bulky protecting group such as triisopropylsilyl (TIPS). This bulky group directs electrophilic substitution to C-3 of the pyrrole ring. Thus, reaction with copper isocyanate followed by sodium borohydride reduction and then fluoride induced TIPS deprotection can afford 3-mercaptopyrroles. Sulfonation of N-protected pyrrole with pyridine sulfur trioxide complex can again be directed to C-3 of the pyrrole to afford, after TIPS deprotection, the 3-sulfonic acids.

Another general method of pyrrole synthesis that can be used to prepare compounds of the present invention is shown in Scheme 5. This approach (Cushman et. al. J. Org. Chem. 1996, 61, 4999) uses N-protected a-aminoketones and N-protected α-aminoaldehydes which are readily available from α-amino acids by initial preparation of the N-methoxy-N-methylamides followed by addition of an alkyl Grignard reagent (to produce ketones) or by reduction with a hydride reducing agent such as lithium aluminum hydride or diisobutylaluminum hydride. These aldehydes and ketones can be allowed to react with the enolates of additional ketones to afford intermediate aldol addition products which under acidic conditions cyclize to form pyrroles. The reacting partners in this approach can be of wide scope and can be chosen so that one skilled in the art will be able to prepare varied pyrroles.

Another very general method of pyrrole synthesis useful for preparing compounds of the present invention is the Paal-Knorr reaction shown in Scheme 6. This reaction involves the reacting 1,4-diketones or 1,4-ketoaldehydes with primary amines to afford pyrroles. The starting 1,4-diketones and 1,4-ketoaldehydes can be prepared using standard enolate chemistry or by other procedures which are familiar to those skilled in the art of organic synthesis. The reaction is of wide scope and the starting materials can be chosen so that a variety of pyrroles can be prepared.

In Scheme 7 is shown how the compounds of Schemes 1-6 wherein R^(e) is a carboxylic ester group can be converted into compounds containing the Z—A—B residue. For the amide linker (Formula I, Z=—CONH—), when R^(e)=carboalkoxy, it can be hydrolyzed to the acid under either basic or acidic conditions depending on the substitution pattern, as described previously. Formation of the acid chloride with thionyl chloride followed by the addition of an appropriate amine H₂N—A—B can afford the amide-linked compounds. Alternatively, the acid can be combined with amine H₂N—A—B in the presence of a suitable peptide coupling agent, such as BOP-Cl, HBTU or DCC. In another method the ester can be directly coupled with an aluminum reagent, prepared by the addition of trimethylaluminum to the amine H₂N—A—B.

To form ether- or thioether-linked compounds of Formula I (Z=—CH₂O—, —CH₂S—) the acid can be reduced to the alcohol. Preferred procedures for this transformation are reduction with borane THF complex, or a procedure involving the reduction of the mixed anhydride with sodium borohydride (IBCF=isobutyl chloroformate and NMM=N-methylmorpholine). Completion of the ether and thioether linked compounds of Formula I can readily be accomplished by the Mitsonobu protocol with an appropriate phenol, thiophenol or hydroxy- or mercaptoheterocycle HX—A—B (X=O,S) (Formula I, A=aryl or heteroaryl). Other ethers or thioethers (X=O,S) can be prepared following initial conversion of the alcohol to a suitable leaving group, such as tosylate. Where X=S, thioethers can be further oxidized to prepare the sulfones (Formula I, Z=—CH₂SO₂—).

To prepare the amine-linked compounds of Formula I (Z=—CH₂NH—) the alcohol can be oxidized to the aldehyde by a number of procedures, two preferred methods of which are the Swern oxidation and oxidation with pyridinium chlorochromate (PCC). Alternatively, the aldehyde may be directly prepared by direct formylation of the pyrrole ring by the Vilsmeier-Haack procedure in certain cases, as described in previous schemes. Reductive amination of the aldehyde with an appropriate amine H₂N—A—B and sodium cyanoborohydride can then afford the amine linked compounds.

The aldehyde also can be used to prepare the ketone-linked compounds of Formula I (Z=—COCH₂—). Treatment with an organometallic species can afford the alcohol. The organometallic species (wherein M=magnesium or zinc) can preferably be prepared from the corresponding halide by treatment with metallic magnesium or zinc. These reagents should readily react with aldehydes to afford alcohols. Oxidation of the alcohol by any of a number of procedures, such as the Swern oxidation or PCC oxidation, can afford the ketones-linked compounds.

Additional compounds of Formula I in which the linking group m/z contains a nitrogen atom attached to ring M can be prepared by the procedures described in Scheme 8. The amines can be converted to sulfonamides (Formula I, m/z-NHSO₂—) by treatment with an appropriate sulfonyl chloride B—A—SO₂Cl in 10 the presence of a base such as triethylamine. The amines can be converted into amides (Formula I, Z=—NHCO—) by treatment with an appropriate acid chloride Cl—CO—A—B in the presence of a base or by treatment with an appropriate carboxylic acid HO—CO—A—B in the presence of a suitable peptide coupling agent, such as DCC, HBTU or BOP. The amines can also be converted into amine-linked compounds (Formula I, Z=—NHCH₂—) by reductive amination with an appropriate aldehyde OHC—A—B.

Additional compounds of Formula I in which the linking group Z contains a sulfur atom attached to ring M can be prepared by the procedures described in Scheme 9. Treatment of sulfonic acids with phosphorous pentachloride followed by treatment with an appropriate amine H₂N—A—B can afford sulfonamide-linked compounds (Formula I, Z=—SO₂NH—). The thiols can be alkylated with a suitable alkylating reagent in the presence of a base to afford thioethers (Formula I, Z=—SCH₂—). These compounds can be further oxidized by a variety of reagents to afford the sulfone-linked compounds (Formula I, Z=—SO₂CH₂—).

Compounds of Formula I wherein ring M is an imidazole can be formed using procedures described in Schemes 10-16. N-Substituted imidazole derivatives can be made by the general procedure shown in Scheme 10, wherein V′ is either V or a precusor of (CH₂)_(n)V, V is nitro, amino, thio, hydroxy, sulfonic acid, sulfonic ester, sulfonyl chloride, ester, acid, or halide, n is 0 and 1, and PG is either a hydrogen or a protecting group. Substitution can be achieved by coupling an imidazole with a halogen containing fragment Q—E—G-Hal in the presence of a catalyst, such as base, Cu/CuBr/base, or Pd/base, followed by conversion of V′ to (CH₂)_(n)V. Then, Q can be converted to D, and finally V can be converted to —Z—A—B following the procedures outlined in Schemes 7-9. Alternatively, V can be converted to Z—A—B followed by deprotection of N. This product can then be coupled as before to obtain the desired imidazole.

One way to make amidino-phenyl-imidazole derivatives is shown in Scheme 11. 4-Imidazole carboxylic acid can be treated with thionyl chloride and then coupled with H₂N—A—B in the presence of a base and then be heated with 3-fluorobenzonitrile in the presence of a base. The Pinner reaction using standard procedures known to those of skill in the art can be used to form the amidino group.

1,2-Disubstituted and 1,5-disubstituted imidazole derivatives can be made by the general procedures described in Scheme 12, wherein R^(1b) is either a hydrogen or an alkyl group and U is aldehyde, ester, acid, amide, amino, thiol, hydroxy, sulfonic acid, sulfonic ester, sulfonyl chloride, or methylene halide. Step a involves coupling in the presence of a catalyst, such as base, Cu/CuBr/base, or Pd/base. When R^(1b) is a hydrogen, it can be deprotonated with a lithium base and trapped by formate, formamide, carbon dioxide, sulfonyl chloride (sulfur dioxide and then chlorine), or isocyanate to give 1,2-disubstituted imidazoles (Route b1). Also, in Route b1 when R^(1b) is CH₃, it can be oxidized with SeO₂, MnO₂, NaIO₄/cat. RhCl₃, or NBS to form U. When R^(1b) is hydrogen, sequential deprotonation and quenching with a lithium base and trimethysilyl chloride, followed by a second deprotonation with a lithium base and quenching with formate, formamide, carbon dioxide, sulfonyl chloride (sulfur dioxide and then chlorine), or isocyanate can afford 1,5-disubstituted imidazoles (Route b2). When R^(1b) is not hydrogen, the procedure of Route b2 can again be used to form 1,5-disubstituted imidazoles (Route b3).

A preferred way of making 1,2-disubstituted and 1,5-disubstituted imidazole derivatives is shown in Scheme 13. Imidazole can be heated with 3-fluorobenzonitrile in the presence of a base. The coupled product can then be treated with an alkyl lithium base and quenched with ClCO₂Me to give the 1,2-disubstituted compound. Further treatment with a solution prepared of H₂N—A—B in trimethylaluminum can give the amide, which can be further modified via the Pinner reaction to form the desired compound. The 1,5-disubstituted compounds can be made using the same procedure, except that the initial anion is protected and a second anion is formed which is then quenched as noted above. Further modifications can follow the same procedures as the 1,2-disubstituted compounds.

Another way of making 1,2-disubstituted imidazole derivatives is described in Scheme 14. By reacting an N-substituted imidazole with a cyanate, the amide can be obtained. This amide can then be coupled with group B as will be described later.

Another means of making 1,5-disubstituted imidazole derivatives is described in Scheme 15. Alkylation with 2-bromoethylacetate and subsequent reaction with Gold's reagent in the presence of a base, such as NaOMe, or LDA, can form ester substituted imidazoles which can be further modified as previously discribed.

A general procedure to make 2,4,5-trisubstituted or 4,5-disubstituted-imidazole derivatives is shown in Scheme 16. After metal halogen exchange of the Q—E—G fragment, it can be reacted with the amide shown, brominated with NBS and cyclized with excess NH₃ and R^(1a)CO₂H to afford an imidazole. This can then be modified as before.

A general procedure to make 4,5-disubstituted triazole derivatives is described in Scheme 17. Ethyl propiolate can be substituted in the presence of CuI/Pd and then reacted with NaN₃ to form a triazole. The triazole can be converted as described previously.

The tetrazole compounds of the present invention where Z is —CONH— can be prepared as exemplified in Scheme 18. An appropiately substituted amine can be acylated with ethyl oxalyl chloride. The resulting amide can be converted to the tetrazole either by the methods described by Duncia (J. Org. Chem. 1991, 2395-2400) or Thomas (Synthesis 1993, 767-768). The amide can be converted to the iminoyl chloride first and the reacted with NaN₃ to form the 5-carboethoxytetrazole (J. Org. Chem. 1993, 58, 32-35 and Bioorg. & Med. Chem. Lett. 1996, 6, 1015-1020). The 5-carboethoxytetrazole can then be further modified as described in Scheme 7.

The tetrazole compounds of the present invention where Z is —CO— can also be prepared via iminoyl chloride (Chem. Ber. 1961, 94, 1116 and J. Org. Chem. 1976, 41, 1073) using an appropriately substituted acyl chloride as starting material. The ketone-linker can be reduced to compounds wherein Z is alkyl.

The methods described in Scheme 18 can also be used to synthesize compounds where the E—Q is linked to the carbon atom of the tetrazole as shown in Scheme 19. The 5-substituted tetrazole can then be alkylated or acylated to give the desired products.

The tetrazole compounds of the present invention wherein Z is —SO₂NH—, —S—, —S(O)—, SO₂— can be prepared from the thiol prepared as shown in Scheme 20. Appropiately substituted thioisocyanate can be reacted with sodium azide to give the 5-thiotetrazole (J. Org. Chem. 1967, 32, 3580-3592). The thio-compound can be modified as described in Scheme 9.

The tetrazole compounds of the present invention wherein Z is —O— can be prepared via the same method described in Scheme 20 by using appropiately substituted isocyanate as the starting material. The hydroxy compound can be modified similarity to the thiols described in Scheme 9.

The tetrazole compounds of the present invention wherein Z is —NH—, —NHCO—, —NHSO₂— can be prepared from 5-aminotetrazole, which can be prepared by Smiles Rearrangement as shown in Scheme 21. The thio-compound prepared as described in Scheme 20 can be alkylated with 2-chloroacetamide. The resulting compound can then be refluxed in ethanolic sodium hydroxide to give the corresponding 5-amino-tetrazole (Chem. Pharm. Bull. 1991, 39, 3331-3334). The resulting 5-amino-tetrazole can then be alkylated or acylated to form the desired products.

Pyrazoles of Formula I (such as those described in Scheme 22) can be prepared by the condensation of an appropriately substituted hydrazine with a variety of diketo esters. Condensations of this type typically afford a mixture of pyrazole regioisomers which can be effectively separated via silica gel column chromatography. The esters can be converted to Z—A—B as previously described.

Alternatively, if in Scheme 22, the starting diketone contains CH₃ in place of CO₂Et, then the resulting methyl pyrazole can be separated and oxidized as in Route b1 in Scheme 12 to form the pyrazole carboxylic acid.

When ketoimidates are used for condensations with hydrazines the corresponding pyrazole amino esters are obtained (Scheme 23). Conversion of these intermediates to the final compounds of formula I can then be accomplished by the protection of the amino functionality with a suitable protecting group or by derivatization (e.g. sulfonamide) and then modifying the ester as previously noted.

As shown in Scheme 24, pyrazoles wherein the 4-position is substituted can be prepared by bromination (bromine or NBS in either dichloromethane or acetic acid) of the initial pyrazole. Conversion of 4-bromo-pyrazole to 4-carboxylic acid pyrazole can be accomplished by a number of methods commonly known to those in the art of organic synthesis. Further manipulations as previously described can afford pyrazoles of the present invention.

Pyrazoles can also be prepared according to method described in Scheme 25. The bromo-pyrazoles are formed as in Scheme 24. QE can then be coupled using palladium catalepsy Suzuki cross-coupling methodology. Further modification is achieved as previously described.

5-substituted phenylpyrazoles can be prepared by the method shown in Scheme 26. Conversion of the 5-hydroxy pyrazole to its triflate (triflic anhydride, lutidine in dichloromethane) or bromide (POBr₃) followed by palladium Suzuki cross-coupling with an apppropriately substituted phenylboronic acid should then afford 5-substituted pyrazoles. Conversion of this intermediate to the 4-bromo derivative followed by its carbonylation as described in Scheme 24 should then afford the appropriate ester which can be further afford the compounds of formula I.

1-Substituted-1,2,3-triazoles of the present invention can be prepared by the treatment of an appropriately substituted azide with a variety of dipolarophiles (Tetrahedron 1971, 27, 845 and J. Amer. Chem. Soc. 1951, 73, 1207) as shown in Scheme 27. Typically a mixture of regioisomers are obtained which can be easily separated and elaborated to the triazole carboxylic acids. Further transformations as previously described can then afford the compounds of the present invention.

1,2,4-Triazoles of the present invention can be obtained by the methodology of Huisgen et al (Liebigs Ann. Chem. 1962, 653, 105) by the cycloaddition of nitriliminium species (derived from the treatment of triethylamine and chloro hydrazone) and an appropriate nitrile dipolarophile (Scheme 28). This methodology provides a wide variety of 1,2,4 triazoles with a varied substitution pattern at the 1, 3, and 5 positions.

1,2,4 Triazoles can also be prepared by the methodology of Zecchi et al (Synthesis 1986, 9, 772) by an aza Wittig condensation (Scheme 29).

1,2,4-Triazoles wherein the —E—D(Q) substituent is at the 5-position of the triazole can be obtained as shown in Scheme 30.

1,3,4-Triazoles of the present invention can be obtained via the methodology of Moderhack et al (J. Prakt. Chem. 1996, 338, 169). As shown in Scheme 31, this reaction involves the condensation of a carbazide with an appropriately substituted commercially available thioisocyanate to form the cyclic thiourea derivative. Alkylation or nucleophilic displacement reactions on the thiono-urea intermediate can then afford a thio-alkyl or aryl intermediate which can be hydrolysed, oxidized and decarboxylated to the 5-H 2-thio-triazole intermediate which can be converted to the compounds of the present invention. Alternatively the thiono-urea intermediate can be oxidized directly to the 2-H triazole which can then be converted to the ester and modified as previously described. The thiono-urea intermediate can also be oxidized to the sulfonyl chloride by methods shown previously.

The imidazole core shown in Scheme 32 can be prepared by the condensation of 3-cyanoaniline with n-butylglyoxylate to afford the imine which can then be treated with TosylMIC in basic methanol to afford the desired imidazole compound. Coupling of the ester under standard conitions then affords a variety of analogs which then can be further manipulated to afford e.g. the benzylamine or the benzamidines.

Compounds of the present invention wherein AB is a biphenylamine or similar amine may be prepared as shown in Scheme 33. 4-Bromoaniline can be protected as Boc-derivative and coupled to a phenylboronic acid under Suzuki conditions (Bioorg. Med. Chem. Lett. 1994, 189). Deprotection with TFA provides the aminobiphenyl compound. Other similar amines wherein A and/or B are heterocycles can be prepared by the same method using appropiately substituted boronic acids and arylbromide. The bromoaniline can also be linked to the core ring structures first as described above, and then undergo a Suzuki reaction to give the desired product.

Compounds of the present invention wherein A—B is A—X—Y can be prepared like the piperazine derivative shown in Scheme 34.

Scheme 35 shows how one can couple cyclic groups wherein X=NH, O, or S.

When B is defined as X—Y, the following description applies. Groups A and B are available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practioners skilled in the art of organic synthesis. The required reactive functional groups appended to analogs of A and B are also available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practioners skilled in the art of organic synthesis. In the tables that follow the chemistry required to effect the coupling of A to B is outlined.

TABLE A Preparation of Amide, Ester, Urea, Sulfonamide and Sulfuide linkages between A and B. then the reactive to give the Rxn. substituent of following product No. if A contains: Y is: A-X-Y: 1 A-NHR² as a ClC(O)—Y A-NR²—C(O)—Y substituent 2 a secondary NH ClC(O)—Y A-C(O)—Y as part of a ring or chain 3 A-OH as a ClC(O)—Y A-O—C(O)—Y substituent 4 A-NHR² as a ClC(O)—CR²R^(2a)—Y A-NR²—C(O)—CR²R^(2a)—Y substituent 5 a secondary NH ClC(O)—CR²R^(2a)—Y A-C(O)—CR²R^(2a)—Y as part of a ring or chain 6 A-OH as a ClC(O)—CR²R^(2a)—Y A-O—C(O)—CR²R^(2a)—Y substituent 7 A-NHR³ as a ClC(O)NR²—Y A-NR²—C(O)NR²—Y substituent 8 a secondary NH ClC(O)NR²—Y A-C(O)NR²—Y as part of a ring or chain 9 A-OH as a ClC(O)NR²—Y A-O—C(O)NR²—Y substituent 10 A-NHR² as a ClSO₂—Y A-NR²—SO₂—Y substituent 11 a secondary NH ClSO₂—Y A-SO₂—Y as part of a ring or chain 12 A-NHR² as a ClSO₂—CR²R^(2a)—Y A-NR²—SO₂—CR²R^(2a)—Y substituent 13 a secondary NH ClSO₂—CR²R^(2a)—Y A-SO₂—CR²R^(2a)—Y as part of a ring or chain 14 A-NHR² as a ClSO₂—NR²—Y A-NR²—SO₂—NR²—Y substituent 15 a secondary NH ClSO₂—NR²—Y A-SO₂—NR²—Y as part of a ring or chain 16 A-C(O)Cl HO—Y as a A-C(O)—O—Y substituent 17 A-C(O)Cl NHR²—Y as a A-C(O)—NR²—Y substituent 18 A-C(O)Cl a secondary NH A-C(O)—Y as part of a ring or chain 19 A-CR²R^(2a)C(O)Cl HO—Y as a A-CR²R^(2a)C(O)—O—Y substituent 20 A-CR²R^(2a)C(O)Cl NHR²—Y as a A-CR²R^(2a)C(O)—NR²—Y substituent 21 A-CR²R^(2a)C(O)Cl a secondary NH A-CR²R^(2a)C(O)—Y as part of a ring or chain 22 A-SO₂Cl NHR²—Y as a A-SO₂—NR²—Y substituent 23 A-SO₂Cl a secondary NH A-SO₂—Y as part of a ring or chain 24 A-CR²R^(2a)SO₂Cl NHR²—Y as a A-CR²R^(2a)SO₂—NR²—Y substituent 25 A-CR²R^(2a)SO₂Cl a secondary NH A-CR²R^(2a)SO₂—Y as part of a ring or chain

The chemistry of Table A can be carried out in aprotic solvents such as a chlorocarbon, pyridine, benzene or toluene, at temperatures ranging from −20° C. to the reflux point of the solvent and with or without a trialkylamine base.

TABLE B Preparation of ketone linkages between A and B. then the reactive to give the Rxn. substituent of following product No. if A contains: Y is: A-X-Y: 1 A-C(O)Cl BrMg—Y A-C(O)—Y 2 A-CR²R^(2a)C(O)Cl BrMg—Y A-CR²R^(2a) ₂C(O)—Y 3 A-C(O)Cl BrMgCR²R^(2a)—Y A-C(O)CR²R^(2a)—Y 4 A-CR²R^(2a)C(O)Cl BrMgCR²R^(2a)—Y A-CR²R^(2a)C(O)CR²R^(2a—) Y

The coupling chemistry of Table B can be carried out by a variety of methods. The Grignard reagent required for Y is prepared from a halogen analog of Y in dry ether, dimethoxyethane or tetrahydrofuran at 0° C. to the reflux point of the solvent. This Grignard reagent can be reacted directly under very controlled conditions, that is low temperature (−20° C. or lower) and with a large excess of acid chloride or with catalytic or stoichiometric copper bromide.dimethyl sulfide complex in dimethyl sulfide as a solvent or with a variant thereof. Other methods available include transforming the Grignard reagent to the cadmium reagent and coupling according to the procedure of Carson and Prout (Org. Syn. Col. Vol. 3 (1955) 601) or a coupling mediated by Fe(acac)₃ according to Fiandanese et al. (Tetrahedron Lett., (1984) 4805), or a coupling mediated by manganese (II) catalysis (Cahiez and Laboue, Tetrahedron Lett., 33(31), (1992) 4437).

TABLE C Preparation of ether and thioether linkages between A and B then the reactive to give the Rxn. substituent of following No. if A contains: Y is: product A-X-Y 1 A-OH Br—Y A-O—Y 2 A-CR²R^(2a)—OH Br—Y A-CR²R^(2a)O—Y 3 A-OH Br—CR²R^(2a)—Y A-OCR²R^(2a)—Y 4 A-SH Br—Y A-S—Y 5 A-CR²R^(2a)—SH Br—Y A-CR²R^(2a)S—Y 6 A-SH Br—CR²R^(2a)—Y A-SCR²R^(2a)—Y

The ether and thioether linkages of Table C can be prepared by reacting the two components in a polar aprotic solvent such as acetone, dimethylformamide or dimethylsulfoxide in the presence of a base such as potassium carbonate, sodium hydride or potassium t-butoxide at temperature ranging from ambient temperature to the reflux point of the solvent used.

TABLE D Preparation of —SO— and —SO2— linkages from thioethers of Table C. and it is oxidized and it is oxidized with m-chloroper- with Alumina (wet)/ benzoic acid (Satoh if the Oxone (Greenhalgh, et al., Chem. Lett. Rxn. starting Synlett, (1992) 235) (1992) 381), the No. material is: the product is: product is: 1 A-S—Y A-S(O)—Y A-SO₂—Y 2 A-CR²R^(2a)S—Y A-CR²R^(2a)S(O)—Y A-CR²R^(2a)SO₂—Y 3 A-SCR²R^(2a)—Y A-S(O)CR²R^(2a)—Y A-SO₂CR²R^(2a)—Y

The thioethers of Table C serve as a convenient starting material for the preparation of the sulfoxide and sulfone analogs of Table D. A combination of wet alumina and oxone can provide a reliable reagent for the oxidation of the thioether to the sulfoxide while m-chloroperbenzoic acid oxidation will give the sulfone.

TABLE E Methods of Preparing Group E Rxn Q D is to be then a transformation that may be used is: 1 —CN —C(═NH)NH2

2 —CN —CN2NH2

3 —CO2H —CH2NH2

4 —CO2H —NH2

In Table E several methods of transforming a functional group Q into group D of Formula 1 are shown. While not all possible functional groups for Q and D are listed and the synthetic methods suggested are not comprehensive, Table E is meant to illustrate strategies and transformations available to a practitioner skilled in the art of organic synthesis for preparing compounds of Formula 1. In reaction 1 of Table E the transformation of a nitrile into an amidine by the Pinner methodology is shown; in reaction 2 the direct reduction of a nitrile by a hydride reducing agent to a methylene amine is illustrated. In reaction 3, the utility of a carboxylic acid, which may be readily derived from its ester or a nitrile if necessary, in the preparation of a methylene amine is shown. This synthetic route is exceptionally flexible because of the several stable intermediates prepared en route to the final product. As outlined, formation of an activated analog, such as the mixed anhydride, allows for the mild reduction of the acid to the methylene alcohol, this may in turn be transformed into a leaving group by sulfonylation or halogenation or protected with a suitable protecting group to be transformed later in the synthesis as the chemistry demands. Once the methylene alcohol is so activated, displacement by an efficient nitrogen nucleophile, such as azide anion, can again provide another suitably stable analog,—the methylene azide—which may be used as a protected form of the methylene amine or transformed directly into the methylene amine group by reduction. Reaction 4 addresses the problem of appending the amine functionality directly through a bond to group E of Formula 1. Once again, the carboxylic acid provides a convenient entre into this selection for group D. The well-know Curtius rearrangement is illustrated here; an activated acid analog can be used to form an acyl azide which upon thermal decomposition is rearranged to the corresponding isocyanate. The isocyanate intermediate may then be captured as a stable carbamate by the addition of a suitable alcohol and further heating. This carbamate can be used as a stable protecting group for the amine or cleaved directly to the desired D. Alternatively, it may be convenient to quench the isocyanate intermediate with water to give the amine directly.

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES Example 1 3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-sulfamido-[1,1′]-biphen-4-yl))carboxyamide, trifluoroacetic acid salt

Part A: 2-Carboxy-4-methoxyphenylhydrazine: 2-Nitro-5-methoxybenzoic acid (5.0 g) in methanol (150 mL) was shaken under an atmosphere of hydrogen (50 psi) in the presence of 10% palladium on carbon catalyst (0.5 g) until hydrogen uptake ceased (ca. 3 h). The methanol solution was purge with nitrogen, filtered through a pad of Celite® and evaporated. There was obtained 4.2 g (25.1 mmol) of the aniline; ESI mass spectrum analysis m/z (relative intensity) 168 (M+H, 100).

The aniline prepared above (4.2 g, 25.1 mmol) in concentrated hydrochloric acid (50 mL) was cooled to 0° C. and sodium nitrite (2.08 g, 30.2 mmol) in cold water (20 mL) was added dropwise. This mixture was stirred at 0° C. for 30 min-1 h then tin(II)chloride dihydrate (17.0 g, 75.4 mmol) in cold concentrated hydrochloric acid (25 mL) was added dropwise. This mixture was allowed to thaw to ambient temperature over 3-5 h then filtered and air dried for several more. The filter cake was broken up and dried further in a vacuum oven at 60° C. overnight. There was obtained 8.76 g of 2-carboxy-4-methoxyphenylhydrazine tin salt.

Part B: Ethyl 2-N-(methoxy)imino-4-oxopentanoate: A mixture of ethyl pentanoate-2,4-dione (24.5 g, 154.9 mmol) and methoxyamine hydrogen chloride (13.58 g, 162.6 mmol) in ethanol (100 mL) was allowed to stand over activated 3 Å molecular sieves (75 g) at ambient temperature for 18 h. Following removal of the molecular sieves by filtration, dichloromethane (100 mL) was added and the reaction filtered. The resulting solution was evaporated and the residue applied to a silica gel column. The title compound was isolated in a homogenous form by elution with 5:1 hexane:ethyl acetate to give 9.09 g of product.

Part C: Ethyl 3-methyl-1-(2-carboxy-4-methoxyphenyl)-1H-pyrazole-5-carboxylate and ethyl 5-methyl-1-(2-carboxy-4-methoxyphenyl)-1H-pyrazole-3-carboxylate: Ethyl 2-N-(methoxy)imino-4-oxopentanoate (1.0 g, 5.35 mmol) and crude 2-carboxy-4-methoxyphenylhydrazine (5.83 g) in acetonitrile (40 mL) and acetic acid (5 mL) was stirred at ambient temperature for 3 h then heated at reflux for an additional 3 h. The reaction was cooled to ambient temperature, diluted with methylene chloride (150 mL) and filtered. The filtrate was evaporated and the product isolated by flash chromatography by elution with 10% methanol in chloroform. This material (1.28 g) co-eluted as a mixture of regiosiomers as evident by proton NMR. ESI mass spectrum analysis m/z (relative intensity) 306 (M+H, 100).

Part D: Ethyl 3-methyl-1-(2-hydroxymethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylate and ethyl 5-methyl-1-(2-hydroxymethyl-4-methoxyphenyl)-1H-pyrazole-3-carboxylate: The mixture of regioisomers prepared in part C (1.28 g, 4.2 mmol) was dissolved in tetrahydrofuran (60 mL) and cooled to 0° C. To the cold solution was added N-methylmorpholine (0.42 g, 4.2 mmol) and isobutylchloroformate (0.57 g, 4.2 mmol). The reaction was stirred for 30 min at 0° C., the precipitate removed by filtration and the cold solution poured immediately into a cold (5° C.) solution of sodium borohydride (0.48 g, 12.6 mmol) in water (20 mL) and tetrahydrofuran (20 mL). The reaction was allowed to thaw to room temperature over 18 h. The reaction mixture was evaporated, partitioned between ethyl acetate (100 mL) and 1N hydrochloric acid (50 mL), then washed with 5% sodium bicarbonate (50 mL) and brine (50 mL). The organic layer was dried and evaporated; three products were isolated by elution of the crude mixture from a silica gel column with 2:1 hexane:ethyl acetate. The first product to elute was a ring closed lactone (0.14 g); ESI mass spectrum analysis m/z (relative intensity) 245 (M+H, 100). The second product isolated was ethyl 3-methyl-1-(2-hydroxymethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylate (0.18 g) as determined by proton NMR nOe experiments; ESI mass spectrum analysis m/z (relative intensity) 291(M+H, 100). The third product to elute was the regioisomer ethyl 5-methyl-1-(2-hydroxymethyl-4-methoxyphenyl)-1H-pyrazole-3-carboxylate (0.14 g); ESI mass spectrum analysis m/z (relative intensity) 291(M+H, 100).

Part E: Ethyl 3-methyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylate: Ethyl 3-methyl-1-(2-hydroxymethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylate (0.18 g, 0.62 mmol) was dissolved in chloroform (20 mL) then methanesulfonyl chloride (0.3 g, 2.6 mmol) and triethylamine (0.26 g, 2.6 mmol) added. The reaction was complete in 6 h; it was evaporated, dissolved in ethyl acetate (100 mL), washed with 1N hydrochloric acid (50 mL) and brine (50 mL), dried and evaporated to give 0.22 g of product.

The mesylate prepared above (0.22 g, 0.6 mmol) and sodium azide (0.12 g, 1.79 mmol) were dissolved in dimethylformamide (15 mL) and heated for 1.5 h at 60° C., then diluted with brine (50 mL), extracted with ethyl acetate (100 mL), dried and evaporated. There was obtained 0.11 g of ethyl 3-methyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylate; ESI mass spectrum analysis m/z (relative intensity) 316 (M+H, 100).

Part F: 3-Methyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid: Ethyl 3-methyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylate (0.11 g, 0.35 mmol) in ethanol (2 mL) and water (2 mL) was stirred with 50% sodium hydroxide (3 drops) at 45° C. and followed by TLC (1:1 hexane:ethyl acetate). When all of the ester was consumed the reaction was cooled, diluted with brine and washed with ethyl ether (25 mL). The aqueous layer was acidified with 1N hydrochloric acid (pH=1), extracted with ethyl acetate (2×30 mL), dried and evaporated. There was obtained 3-methyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid (0.06 g); ESI mass spectrum analysis m/z (relative intensity) 285 (M+H, 100).

Part G: 3-Methyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-(2-N-t-butylsulfamido)phenyl)phenyl)carboxyamide: 3-Methyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid (0.60 g, 0.21 mmol) in dichloromethane (5 mL) was cooled to 0° C. and oxalyl chloride (0.21 mL of a 2M solution in dichloromethane) and dimethyl formamide (1 drop) were added. The reaction was complete inside of 1 h; it was evaporated and pumped on to remove residual HCl. There was obtained 0.17 g of the acid chloride.

To the acid chloride prepared above (0.17 g, 0.50 mmol) in dichloromethane (3 mL) was added dropwise to an ice-cold solution of 4-(2-N-tertbutylsulfonamido)phenyl aniline (0.15 g, 0.51 mmol), pyridine (0.39 g, 4.4 mmol) and 4,4-dimethylaminopyridine (0.09 g, 0.7 mmol) in dichloromethane (15 mL). The reaction was allowed to warm to ambient temperature over 18 h, then evaporated, dissolved in ethyl acetate (30 mL), washed with 1N hydrochloric acid (20 mL) and dried. Silica gel flash chromatography, eluting with a gradient of 2:1 to 1:1 hexane:ethyl acetate, gave 0.09 g of 3-methyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-(2-N-t-butylsulfamido)phenyl)phenyl)carboxyamide; ESI mass spectrum analysis m/z (relative intensity) 572 (M+H, 100).

Part H: 3-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-sulfamido-[1,1′]-biphen-4-yl))carboxyamide.TFA: 3-Methyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-N-t-butylsulfamido-[1,1′]-biphen-4-yl))carboxyamide (0.09 g, 0.16 mmol) was stirred with tin(II) chloride dihydrate (0.11 g, 0.47 mmol) in methanol (10 mL). When the reaction was complete by TLC (1:1 hexane:ethyl acetate) it was evaporated to give a crude mixture of the aminomethyl product and tin salts weighing 0.39 g. The material was heated at reflux in trifluoroacetic acid (10 mL) for 45 min then evaporated. The residue was partitioned between 1N sodium hydroxide (30 mL) and ethyl acetate (30 mL). The ethyl acetate solution was dried and evaporated to give 0.04 g of crude product. This material was purified further by hplc utilizing gradient elution with a mixture of water:acetonitrile with 0.05% trifluoroacetic acid on a reverse phase C18 (60 Å) column to give 0.010 g of the title compound; mp 184.3° C.; HRMS (M+H)⁺ calc. m/z: 492.170551, obs m/z: 492.171712.

Example 2 5-Methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-3-(N-(2′-sulfamido-[1,1′]-biphen-4-yl))carboxyamide, trifluoroacetic acid salt

The regioisomeric acid prepared in Example 1, ethyl 5-methyl-1-(2-hydroxymethyl-4-methoxyphenyl)-1H-pyrazole-3-carboxylate (0.14 g, 0.48 mmol), was transformed into the azidomethyl analog, coupled with 4-(2-N-tertbutylsulfonamido)phenyl aniline and transformed into 5-methyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-3-(N-(4-(2-sulfamido)phenyl)phenyl)carboxyamide by the same procedures described in Example 1. The final product was purified further by hplc utilizing gradient elution with a mixture of water:acetonitrile with 0.05% trifluoroacetic acid on a reverse phase C18 (60 Å) column; HRMS (M+H)⁺ calc. m/z: 492.170551, obs m/z: 492.169327.

Example 3 3-methyl-1-(2-N,N-dimethylaminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-N-methylsulfamido-[1,1′]-biphen-4-yl))carboxyamide, trifluoroacetic acid salt

3-Methyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-N-t-butylsulfamido-[1,1′]-biphen-4-yl))carboxyamide (0.09 g, 0.16 mmol), prepared in Example 1, was stirred with tin(II) chloride dihydrate (0.11 g, 0.47 mmol) in methanol (10 mL). When the reaction was complete by TLC (1:1 hexane:ethyl acetate) it was evaporated to give a crude mixture of the aminomethyl product and tin salts weighing 0.39 g. A portion of the crude reduction product (0.1 g, 0.20 mmol) prepared above was stirred at ambient temperature with methyl iodide (0.2 mL), and potassium hydrogen carbonate (solid, 0.2 g) in methanol (4 mL) at ambient temperature. After 18 h the reaction was evaporated and stirred with chloroform (30 mL), filtered and evaporated again to give 0.28 g of crude product.

The material from above was heated at reflux in trifluoroacetic acid (10 mL) for 45 min then evaporated. The residue was partitioned between 1N sodium hydroxide (30 mL) and ethyl acetate (30 mL). The ethyl acetate solution was dried and evaporated to give crude product. This material was purified further by hplc utilizing gradient elution with a mixture of water:acetonitrile with 0.05% trifluoroacetic acid on a reverse phase C18 (60 Å) column to give the title compound; mp 114.5° C.; HRMS (M+H)⁺ calc. m/z: 534.217502, obs m/z: 534.218000.

Example 4 3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-sulfamido-[1,1]-biphen-4-yl))carboxyamide, trifluoroacetic acid salt

Part A: 3-Trifluoromethyl-1-(2-carboxy-4-methoxyphenyl)-5-(furan-2-yl)-1H-pyrazole: Crude 2-carboxy-4-methoxyphenylhydrazine (8.88 g), prepared in Example 1, and 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione (7.4 g, 135.9 mmol) in acetic acid (150 mL) was heated at 100° C. for 4 h. The hot reaction mixture was evaporated and the residue stirred in a biphasic mixture of water (150 mL) and chloroform (150 mL). The layers were filtered and separated, the solid percipitate washed several times with additional chloroform (3×50 mL) and the chloroform layer and washings combined, dried and evaporated. There was obtained 3.55 g of 3-trifluoromethyl-1-(2-carboxy-4-methoxyphenyl)-5-(furan-2-yl)-1H-pyrazole; ESI (−ve) mass spectrum analysis m/z (relative intensity) 351 (M−H, 100).

Part B: 3-Trifluoromethyl-1-(2-hydroxymethyl-4-methoxyphenyl)-5-(furan-2-yl)-1H-pyrazole: 3-Trifluoromethyl-1-(2-carboxy-4-methoxyphenyl)-5-(furan-2-yl)-1H-pyrazole (3.55 g, 10.1 mmol) in tetrahydrofuran (100 mL) was cooled to 0° C. then N-methylmorpholine (1.02 g, 10.1 mmol) and isobutyl chloroformate (1.38 g, 10.1 mmol) were added. The reaction mixture was stirred for 30 min at 0° C., filtered and added immediately to a cold solution of sodium borohydride (1.15 g, 30.2 mmol) in water (50 mL) and tetrahydrofuran (50 mL). The reaction mixture was evaporated, partitioned between ethyl acetate (100 mL) and 1N hydrochloric acid (50 mL), then washed with 5% sodium bicarbonate (50 mL) and brine (50 mL). The organic layer was dried and evaporated then purified further by flash chromatography using 4:1 hexane:ethyl acetate as the eluent. There was obtained 1.5 g of 3-trifluoromethyl-1-(2-hydroxymethyl-4-methoxyphenyl)-5-(furan-2-yl)-1H-pyrazole; ESI mass spectrum analysis m/z (relative intensity) 339 (M+H, 100).

Part C: 3-Trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-5-(furan-2-yl)-1H-pyrazole: To a cooled chloroform (50 mL) solution of 3-trifluoromethyl-1-(2-hydroxymethyl-4-methoxyphenyl)-5-(furan-2-yl)-1H-pyrazole (1.5 g, 4.44 mmol) and triethylamine (1.79 g, 17.7 mmol) was added a chloroform solution (10 mL) of methanesulfonyl chloride (2.03 g, 17.7 mmol). The reaction was complete in 4 h. It was evaporated, dissolved in ethyl acetate (100 mL) and the ethyl acetate solution washed with cold 5% NaHSO₄ (50 mL) and cold saturated NaHCO₃ (50 mL). The organic layer was dried and evaporated to give 2.1 g of the mesylate which was used immediately in the next reaction; ESI mass spectrum analysis m/z (relative intensity) 417(M+H, 100).

A mixture of the mesylate prepared above (2.1 g, 5.05 mmol) and sodium azide (0.98 g, 15.1 mmol) in dimethylformamide (40 mL) was heated at 60° C. for 2 h. The reaction mixture was cooled, diluted with brine (100 mL) and extracted with ethyl acetate (100 mL). The ethyl acetate extract was washed with water (5×50 mL) then dried and evaporated. There was obtained 1.43 g of 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-5-(furan-2-yl)-1H-pyrazole; ESI mass spectrum analysis m/z (relative intensity) 364 (M+H, 100).

Part D: 3-Trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid: To 1.43 g of 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-5-(furan-2-yl)-1H-pyrazole (3.9 mmol) in acetone (60 mL) was added potassium permaganate (5.0 g, 27.5 m mol) in water (60 mL). The reaction was heated at 60° C. for 3 h, then cooled to ambient temperature and isopropyl alcohol (60 mL) added. This mixture was stirred for 18 h then filtered through a Celite® pad and washed with copious amounts of isopropyl alcohol. The combined filtrates were evaporated, the residue dissolved in 1N NaOH (50 mL) and washed with ethyl ether (2×50 mL). The basic layer was acidified with 1N HCl (75 mL) and solid NaCl added. The suspension was extracted with EtOAc (3×100 mL); the extracts were dried and evaporated. There was obtained 0.91 g of 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid; ESI (−ve) mass spectrum analysis m/z (relative intensity) 340 (M−H, 100).

Part E: 3-Trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid chloride: 3-Trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid (1.09 g, 3.2 mmol) in dichloromethane (50 mL) was stirred at 0° C. with oxalyl chloride from 3.2 mL of a 2M dichloromethane solution of the reagent and a catalytic amount of DMF (3 drops). The reaction was complete in 3 h, then evaporated and pumped on to remove residual reagent. There was obtained 1.04 g (2.9 mmol) of 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid chloride.

Part F: 3-Trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-(2-N-tertbutylsulfamido-[1,1]-biphen-4-yl))carboxyamide: 3-Trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid chloride prepared above (0.52 g, 1.45 mmol) in dichloromethane (10 mL) was added dropwise to an ice-cold solution of 2-fluoro-4-(2-N-tertbutylsulfonamido)phenyl aniline (0.56 g, 1.74 mmol), pyridine (1.14 g, 14.5 mmol) and 4,4-dimethylaminopyridine (0.21 g, 1.74 mmol) in dichloromethane (30 mL). The reaction was allowed to warm to ambient temperature over 18 h, then evaporated, dissolved in ethyl acetate (100 mL), washed with 1N hydrochloric acid (50 mL) and dried. Silica gel flash chromatography, eluting with 4:1 hexane:ethyl acetate, gave 0.28 g of 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-(2-N-tertbutylsulfamidophenyl)phenyl)carboxyamide; ESI (−ve) mass spectrum analysis m/z (relative intensity) 644 (M−H, 100).

Part G: 3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphen-1-yl)-1H-pyrazole-5-(N-(2-fluoro-4-(2-sulfamido-[1,1]-biphen-4-yl))carboxyamide.TFA: 3-Trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-(2-N-tertbutylsulfamidophenyl)phenyl)carboxyamide (0.28 g, 0.43 mmol) and tin(II)chloride dihydrate (0.29 g, 1.3 mmol) was stirred in methanol (30 mL) for 18 h. The reaction was evaporated and the reduction product (0.60 g) was carried on to the next step without further processing.

The product prepared above was refluxed in trifluoroacetic acid (20 mL) for 30 min, then evaporated. The residue was suspened in 1N NaOH (30 mL), extracted with EtOAc (3×50 mL), dried and evaporated. This material was purified further by hplc utilizing gradient elution with a mixture of water:acetonitrile with 0.05% trifluoroacetic acid on a reverse phase C18 (60 Å) column to give the title compound; mp 103.2° C.; ESI ESI mass spectrum analysis m/z (relative intensity) 564.2 (M+H, 100).

Example 5 3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1]-biphen-4-yl))carboxyamide, trifluoroacetic acid salt

Part A: 3-Trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-(2-methylsulfonylphenyl)phenyl)carboxyamide: 3-Trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid chloride prepared in Example 4 (0.52 g, 1.45 mmol) in dichloromethane (10 mL) was added dropwise to an ice-cold solution of 2-fluoro-4-(2-methylsulfonylphenyl)aniline (0.52 g, 1.74 mmol), pyridine (1.14 g, 14.5 mmol) and 4,4-dimethylaminopyridine (0.21 g, 1.74 mmol) in dichloromethane (30 mL). The reaction was allowed to warm to ambient temperature over 18 h, then evaporated, dissolved in ethyl acetate (100 mL), washed with 1N hydrochloric acid (50 mL) and dried. Silica gel flash chromatography, eluting with a gradient of 5:1 to 1:1 hexane:ethyl acetate, gave 0.46 g of 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2-fluoro-4-(2-methylsulfonylphenyl)phenyl)carboxyamide; ESI mass spectrum analysis m/z (relative intensity) 587 (M+H, 100).

Part B: 3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1]-biphen-4-yl))carboxyamide.TFA: 3-Trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1]-biphen-4-yl))carboxyamide (0.46 g, 0.78 mmol) and tin(II)chloride dihydrate (0.53 g, 2.35 mmol) was stirred in methanol (25 mL) for 18 h. The reaction was evaporated and the residue was suspended in 1N NaOH (50 mL), extracted with EtOAc (3×100 mL), dried and evaporated to give 0.29 g of crude product. This material was purified further by hplc utilizing gradient elution with a mixture of water:acetonitrile with 0.05% trifluoroacetic acid on a reverse phase C18 (60 Å) column to give the title compound; mp 101.5° C.; ESI mass spectrum analysis m/z (relative intensity) 563 (M+H, 100).

Example 6 3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-methylsulfonyl-[1,1]-biphen-4-yl))carboxyamide, trifluoroacetic acid salt

Part A: 3-Trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-methylsulfonyl-[1,1]-biphen-4-yl))carboxyamide: 3-Trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid chloride and 4-(2-methylsulfonylphenyl)aniline were treated in the manner described for Example 5, Part A to give 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-(2-methylsulfonylphenyl)phenyl)carboxyamide.

Part B: 3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-methylsulfonyl-[1,1]-biphen-4-yl))carboxyamide.TFA: 3-Trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-(2-methylsulfonylphenyl)phenyl)carboxyamide was treated in the same manner as Example 5, Part B to give the title compound; HRMS (M+H)⁺ calc. m/z: 545.147037, obs m/z: 545.145700.

Example 7 3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-sulfamido-[1,1]-biphen-4-yl))carboxyamide, trifluoroacetic acid salt

Part A: 3-Trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(2′-N-tertbutylsulfamido-[1,1]-biphen-4-yl))carboxyamide: 3-Trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid chloride and 4-(2-N-tertbutylsulfonamido)phenyl aniline were treated as described in Example 4, Part F to give 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-(2-N-tertbutylsulfamidophenyl)phenyl)carboxyamide.

Part B: 3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphen-1-yl)-1H-pyrazole-5-(N-(2′-sulfamido-[1,1]-biphen-4-yl))carboxyamide.TFA: 3-Trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-(2-N-tertbutylsulfamidophenyl)phenyl)carboxyamide was treated as described in Example 4, Part G to give the title compound; LRMS (M+H)⁺: m/z 546.2.

Example 8 3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-N-pyrrolidinocarbonyl)phenyl)carboxyamide.TFA

Part A: 5-(Furan-2-yl)-3-trifluoromethyl-1-(2-carboxyl-4-methoxyphenyl)-1H-pyrazole: 3-Methoxy-6-aminobenzoic acid (23 g, 138 mmol) in conc. HCl (300 mL) was cooled to 0° C. and NaNO₂ (11.4 g, 165 mmol) in H₂O (50 mL) was added dropwise while the temperature of the reaction was maintained below 10° C. The reaction was stirred at or below 10° C. for 1 h, then SnCl₂.H₂O (92.3 g, 413 mmol) in conc. HCl (125 mL) was added dropwise. The reaction was allowed to thaw to ambient temperature and stirred for 3 h. The precipitate was filtered and air-dried then heated in a vacuum oven for 18 h. There was obtained 71.4 g of 3-methoxy-6-hydrazinobenzoic acid entrained with tin (II) salts.

The hydrazine prepared above (71.4 g) in acetic acid (800 mL) was heated at 45° C. until dissolved, then 4,4,4-trifluoromethyl-1-(2-furyl)-1,3-butanedione (28.42 g, 138 mmol) was added and the mixture heated at reflux for 2.5 h. The reaction was cooled and evaporated to dryness. The residue was partitioned between H₂O (400 mL) and CHCl₃ (400 mL) and stirred for 30 min. The biphasic mixture was filtered, the layers separated and the organic layer dried (Na₂SO₄) and evaporated to give 49.4 g of 5-(furan-2-yl)-3-trifluoromethyl-1-(2-carboxyl-4-methoxyphenyl)-1H-pyrazole; LRMS (ES⁻) M⁻: 351 m/z.

Part B: 3-Trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid: To a solution of 5-(furan-2-yl)-3-trifluoromethyl-1-(2-carboxyl-4-methoxyphenyl)-1H-pyrazole (49.4 g, 140.3 mmol) in THF (600 mL) at 0° C. was added N-methylmorpholine (14.9 g, 147 mmol) and isobutylchloroformate (20.1 g, 147.3 mmol). After 3 h at 0° C., the reaction mixture was filtered into a H₂O: THF (200 mL: 200 mL) solution of NaBH₄ (10.6 g, 280 mmol) at 0° C. After 18 h, the reaction was quenched with 1N HCl (500 mL) then the THF was removed in vaccuo. The remaining aqueous suspension was saturated with solid NaCl and extracted with EtOAc, dried (Na₂SO₄) and evaporated. The crude product was recrystallized from 1-chlorobutane to give 16.8 g of benzyl alcohol product. The mother liquors were applied to a column of flash SiO₂ (500 g) and eluted with 2:1 hexane: EtOAc to give 8.7 g of benzyl alcohol product; LRMS ES⁺ (M+H)⁺: 339 m/z.

The benzyl alcohol product (8.7 g, 25.1 mmol) prepared above and Et₃N (3.1 g, 30.9 mmol) in CH₂Cl₂ (200 mL) was cooled to 0° C. Methanesulfonyl chloride (3.5 g, 30.9 mmol) in CH₂Cl₂ (10 mL) was added dropwise. The cooling bath was removed and the reaction stirred for 3 h. A 5% solution of NaHSO₄ (200 mL) was added, the organic layer was separated, dried and evaporated to give 10.25 g of mesylate.

The mesylate (10.25 g, 24.6 mmol) from above and NaN₃ (4.8 g, 73.8 mmol) in DMF (100 mL) was stirred at ambient temperature for 18 h. The reaction was diluted with brine (500 mL), extracted with EtOAc and the extracts washed with H₂O (5×150 mL). The EtOAc layer was dried (Na₂SO₄) and evaporated to give 8.16 of the azidomethyl compound; LRMS ES⁺ (M+H)⁺: 364 m/z.

The azidomethyl coumpound (23 g, 63.4 mmol) in acetone (400 mL) was heated at 60° C., then KMnO₄ (50 g, 317 mmol) in H₂O (300 mL) was added. After addition was complete, the reaction was heated for 1.5 h. The cooled reaction was filtered through a pad of Celite® and evaporated. The water layer was made basic with 1N NaOH (200 mL) and washed with Et₂O (3×), then acidified with conc. HCl, saturated with solid NaCl and extracted with EtOAc (3×). The EtOAc layer was dried and evaporated to give 15.1 g of 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid; LRMS ES⁻ (M−H)⁻: 340 m/z.

Part C: 3-Trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-N-carboxylpyrrolidino)phenyl)carboxyamide: To 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid (0.44 g, 1.29 mmol) prepared above in CH₂Cl₂ at 0° C. was added a 2M solution of oxalyl chloride in CH₂Cl₂ (2 equivilents, 1.29 mL) followed by a drop of DMF. The ice bath was removed and the reaction stirred for 3 h then evaporated. The resulting acid chloride was combined with N-(4-aminobenzoyl)pyrrolidine (0.32 g, 1.68 mmol) and DMAP (0.47 g, 3.87 mmol) and dissolved in CH₂Cl₂ (20 mL). The reaction was stirred for 18 h, then evaporated and dissolved in EtOAc. The EtOAc layer was washed with 1N HCl and brine, dried (Na₂SO₄) and evaporated. The product was purified further by a column of flash SiO₂ (50 g) eluting with 5-10% MeOH in CHCl₃ to give 0.24 g of 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-N-carboxylpyrrolidino)phenyl)carboxyamide; LRMS ES+ (M+H)+: 514 m/z.

Part D: 3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-N-carboxylpyrrolidino)phenyl)carboxyamide.TFA: A mixture of 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(4-N-carboxylpyrrolidino)phenyl)carboxyamide (0.24 g, 0.27 mmol) and SnCl₂.2H₂O (0.24 g, 0.95 mmol) in MeOH (20 mL) was stirred for 18 h. The reaction was evaporated and dissolved in 1N NaOH. The basic layer was extracted with EtOAc dried and evaporated. The crude product was purified further by HPLC utilizing gradient elution with a mixture of water:acetonitrile with 0.05% trifluoroacetic acid on a reverse phase C18 (60 Å) column to give 31.2 mg of title compound; mp 117.5° C.; HRMS (M+H)⁺ calc. m/z: 488.190950, obs: 488.191005.

Example 9 N-Benzylsulfonyl-4-(3-trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxyamido)piperidine.TFA

3-Trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid prepared in Part B of Example 8 was coupled with N-Benzylsulfonyl-4-aminopiperidine according to the procedure in Part C of Example 8. The title compound was prepared and purified by the method outlined in Part D of Example 8; mp 98.3° C.; HRMS (M+H)⁺ calc. m/z: 552.189236 obs: 552.188800.

Example 10 3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-(2′-sulfonamido)phenyl)pyrid-2-yl)carboxyamide.TFA

3-Trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid prepared in Part B of Example 8 was coupled with 2-amino-5-((2-N-t-butylsulfonamido)phenyl)pyridine according to the procedure in Part C of Example 8. The azidomethyl group was reduced to the aminomethyl group with SnCl₂.2H₂O by the method outlined in Part D of Example 8. The crude reduction product was then refluxed in trifluoroacetic acid (10 mL) for 1 h to remove the t-butyl protecting group. The title compound was isolated by HPLC utilizing gradient elution with a mixture of water:acetonitrile with 0.05% trifluoroacetic acid on a reverse phase C18 (60 Å) column; mp 86.6° C.; HRMS (M+H)⁺ calc. m/z: 547.137535, obs: 547.138200.

Example 11 3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(5-(pyrid-2-yl))pyrid-2-yl)carboxyamide.TFA

3-Trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid prepared in Part B of Example 8 was coupled with 2-amino-5-(pyrid-2-yl)pyridine according to the procedure in Part C of Example 8. The title compound was prepared and purified by the method outlined in Part D of Example 8; mp 48.2° C.; HRMS (M+H)⁺: 469.1602 m/z.

Example 12 N-Benzyl-4-(3-trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxyamido)piperidine.TFA

3-Trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid prepared in Part B of Example 8 was coupled with N-Benzyl-4-aminopiperidine according to the procedure in Part C of Example 8. The title compound was prepared and purified by the method outlined in Part D of Example 8; mp 116.1° C.; HRMS (M+H)⁺: 488.2266 m/z.

Example 13 N-Phenylsulfonyl-4-(3-trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxyamido)piperidine.TFA

3-Trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid prepared in Part B of Example 8 was coupled with N-phenylsulfonyl-4-aminopiperidine according to the procedure in Part C of Example 8. The title compound was prepared and purified by the method outlined in Part D of Example 8; mp 103° C.; HRMS (M+H)⁺: 538.1729 m/z.

Example 14 3-Trifluoromethyl-1-(2-aminomethyl-4-chlorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide.TFA

3-Trifluoromethyl-1-(2-azidomethyl-4-chlorophenyl)-1H-pyrazole-5-carboxylic acid was prepared from 3-chloro-6-aminobenzoic acid by essentially the same method used for 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid in Parts A and B of Example 8. This compound was coupled with 2-fluoro-4-((2-methansulfonyl)phenyl)aniline according to the procedure in Part C of Example 8. The title compound was prepared and purified by the method outlined in Part D of Example 8; mp 97.5° C.; HRMS (M+H)⁺: 567.0891 m/z.

Example 15 3-Trifluoromethyl-1-(2-aminomethyl-4-chlorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-sulfamido-[1,1′]-biphen-4-yl))carboxyamide.TFA

3-Trifluoromethyl-1-(2-azidomethyl-4-chlorophenyl)-1H-pyrazole-5-carboxylic acid was prepared from 3-chloro-6-aminobenzoic acid by essentially the same method used for 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid in Parts A and B of Example 8. This compound was coupled with 2-fluoro-4-((2-N-t-butylsulfonamido)phenyl)aniline according to the procedure in Part C of Example 8. The azidomethyl group was reduced to the aminomethyl group with SnCl₂.2H₂O by the method outlined in Part D of Example 8. The crude reduction product was then refluxed in trifluoroacetic acid (10 mL) for 1 h to remove the t-butyl protecting group. The title compound was isolated by HPLC utilizing gradient elution with a mixture of water:acetonitrile with 0.05% trifluoroacetic acid on a reverse phase C18 (60 Å) column; mp 128° C.; HRMS (M+H)⁺: 568.0832 m/z.

Example 16 3-Trifluoromethyl-1-(2-aminomethyl-5-chlorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide.TFA

3-Trifluoromethyl-1-(2-azidomethyl-5-chlorophenyl)-1H-pyrazole-5-carboxylic acid was prepared from 4-chloro-6-aminobenzoic acid by essentially the same method used for 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid in Parts A and B of Example 8. This compound was coupled with 2-fluoro-4-((2-methansulfonyl)phenyl)aniline according to the procedure in Part C of Example 8. The title compound was prepared and purified by the method outlined in Part D of Example 8; mp 99.7° C.; HRMS (M+H)⁺: 567.0859 m/z.

Example 17 3-Trifluoromethyl-1-(2-aminmoethyl-4-chlorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-sulfamido-[1,1′]-biphen-4-yl))carboxyamide.TFA

3-Trifluoromethyl-1-(2-azidomethyl-5-chlorophenyl)-1H-pyrazole-5-carboxylic acid was prepared from 4-chloro-6-aminobenzoic acid by essentially the same method used for 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid in Parts A and B of Example 8. This compound was coupled with 2-fluoro-4-((2-N-t-butylsulfonamido)phenyl)aniline according to the procedure in Part C of Example 8. The azidomethyl group was reduced to the aminomethyl group with SnCl₂.2H₂O by the method outlined in Part D of Example 8. The crude reduction product was then refluxed in trifluoroacetic acid (10 mL) for 1 h to remove the t-butyl protecting group. The title compound was isolated by HPLC utilizing gradient elution with a mixture of water:acetonitrile with 0.05% trifluoroacetic acid on a reverse phase C18 (60 Å) column; mp 127.4° C.; HRMS (M+H)⁺: 568.0837 m/z.

Example 18 3-Trifluoromethyl-1-(2-aminomethyl-4-fluorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide.TFA

3-Trifluoromethyl-1-(2-azidomethyl-4-fluorophenyl)-1H-pyrazole-5-carboxylic acid was prepared from 3-fluoro-6-aminobenzoic acid by essentially the same method used for 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid in Parts A and B of Example 8. This compound was coupled with 2-fluoro-4-((2-methansulfonyl)phenyl)aniline according to the procedure in Part C of Example 8. The title compound was prepared and purified by the method outlined in Part D of Example 8; mp 125° C.; HRMS (M+H)⁺: 551.1177 m/z.

Example 19 3-Trifluoromethyl-1-(2-aminomethyl-4-fluorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-sulfamido-[1,1′]-biphen-4-yl))carboxyamide.TFA

3-Trifluoromethyl-1-(2-azidomethyl-4-fluorophenyl)-1H-pyrazole-5-carboxylic acid was prepared from 3-fluoro-6-aminobenzoic acid by essentially the same method used for 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid in Parts A and B of Example 8. This compound was coupled with 2-fluoro-4-((2-N-t-butylsulfonamido)phenyl)aniline according to the procedure in Part C of Example 8. The azidomethyl group was reduced to the aminomethyl group with SnCl₂.2H₂O by the method outlined in Part D of Example 8. The crude reduction product was then refluxed in trifluoroacetic acid (10 mL) for 1 h to remove the t-butyl protecting group. The title compound was isolated by HPLC utilizing gradient elution with a mixture of water:acetonitrile with 0.05% trifluoroacetic acid on a reverse phase C18 (60 Å) column; mp 113.1° C.; HRMS (M+H)⁺: 552.1112 m/z.

Example 20 3-Trifluoromethyl-1-(2-aminomethyl-5-fluorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide.TFA

3-Trifluoromethyl-1-(2-azidomethyl-5-fluorophenyl)-1H-pyrazole-5-carboxylic acid was prepared from 4-fluoro-6-aminobenzoic acid by essentially the same method used for 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1-H-pyrazole-5-carboxylic acid in Parts A and B of Example 8. This compound was coupled with 2-fluoro-4-((2-methansulfonyl)phenyl)aniline according to the procedure in Part C of Example 8. The title compound was prepared and purified by the method outlined in Part D of Example 8; mp 97.2° C.; HRMS (M+H)⁺: 551.1179 m/z.

Example 21 3-Trifluoromethyl-1-(2-aminomethyl-5-fluorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-sulfamido-[1,1′]-biphen-4-yl))carboxyamide.TFA

3-Trifluoromethyl-1-(2-azidomethyl-5-fluorophenyl)-1H-pyrazole-5-carboxylic acid was prepared from 4-fluoro-6-aminobenzoic acid by essentially the same method used for 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid in Parts A and B of Example 8. This compound was coupled with 2-fluoro-4-((2-N-t-butylsulfonamido)phenyl)aniline according to the procedure in Part C of Example 8. The azidomethyl group was reduced to the aminomethyl group with SnCl₂.2H₂O by the method outlined in Part D of Example 8. The crude reduction product was then refluxed in trifluoroacetic acid (10 mL) for 1 h to remove the t-butyl protecting group. The title compound was isolated by HPLC utilizing gradient elution with a mixture of water:acetonitrile with 0.05% trifluoroacetic acid on a reverse phase C18 (60 Å) column; mp 101° C.; HRMS (M+H)⁺: 552.1120 m/z.

Example 22 3-Trifluoromethyl-1-(2-aminomethyl-4,5-difluorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide.TFA

3-Trifluoromethyl-1-(2-azidomethyl-4,5-difluorophenyl)-1H-pyrazole-5-carboxylic acid was prepared from 3,4-difluoro-6-aminobenzoic acid by essentially the same method used for 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid in Parts A and B of Example 8. This compound was coupled with 2-fluoro-4-((2-methansulfonyl)phenyl)aniline according to the procedure in Part C of Example 8. The title compound was prepared and purified by the method outlined in Part D of Example 8; HRMS (M+H)⁺: 569.1082 m/z.

Example 23 3-Trifluoromethyl-1-(2-aminomethyl-4,5-difluorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-sulfamido-[1,1′]-biphen-4-yl))carboxyamide.TFA

3-Trifluoromethyl-1-(2-azidomethyl-4,5-difluorophenyl)-1H-pyrazole-5-carboxylic acid was prepared from 3,4-difluoro-6-aminobenzoic acid by essentially the same method used for 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid in Parts A and B of Example 8. This compound was coupled with 2-fluoro-4-((2-N-t-butylsulfonamido)phenyl)aniline according to the procedure in Part C of Example 8. The azidomethyl group was reduced to the aminomethyl group with SnCl₂.2H₂O by the method outlined in Part D of Example 8. The crude reduction product was then refluxed in trifluoroacetic acid (10 mL) for 1 h to remove the t-butyl protecting group. The title compound was isolated by HPLC utilizing gradient elution with a mixture of water:acetonitrile with 0.05% trifluoroacetic acid on a reverse phase C18 (60 Å) column; mp 118.7° C.; HRMS (M+H)⁺: 570.1038 m/z.

Example 24 3-Trifluoromethyl-1-(2-aminomethyl-3-fluorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide.TFA

3-Trifluoromethyl-1-(2-azidomethyl-3-fluorophenyl)-1H-pyrazole-5-carboxylic acid was prepared from 2-fluoro-6-aminobenzoic acid by essentially the same method used for 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid in Parts A and B of Example 8. This compound was coupled with 2-fluoro-4-((2-methansulfonyl)phenyl)aniline according to the procedure in Part C of Example 8. The title compound was prepared and purified by the method outlined in Part D of Example 8; mp 105.1° C.; HRMS (M+H)⁺: 551.1180 m/z.

Example 25 3-Trifluoromethyl-1-(2-aminomethyl-3-fluorophenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-sulfamido-[1,1′]-biphen-4-yl))carboxyamide.TFA

3-Trifluoromethyl-1-(2-azidomethyl-3-fluorophenyl)-1H-pyrazole-5-carboxylic acid was prepared from 2-fluoro-6-aminobenzoic acid by essentially the same method used for 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid in Parts A and B of Example 8. This compound was coupled with 2-fluoro-4-((2-N-t-butylsulfonamido)phenyl)aniline according to the procedure in Part C of Example 8. The azidomethyl group was reduced to the aminomethyl group with SnCl₂.2H₂O by the method outlined in Part D of Example 8. The crude reduction product was then refluxed in trifluoroacetic acid (10 mL) for 1 h to remove the t-butyl protecting group. The title compound was isolated by HPLC utilizing gradient elution with a mixture of water:acetonitrile with 0.05% trifluoroacetic acid on a reverse phase C18 (60 Å) column; mp 115.8° C.; HRMS (M+H)⁺: 552.1111 m/z.

Example 26 3-Trifluoromethyl-1-(2-aminomethyl-4-fluorophenyl)-1H-pyrazole-5-(N-(4-(2-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide.TFA

3-Trifluoromethyl-1-(2-azidomethyl-4-fluorophenyl)-1H-pyrazole-5-carboxylic acid was prepared from 3-fluoro-6-aminobenzoic acid by essentially the same method used for 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid in Parts A and B of Example 8. This compound was coupled with 4-((2-methansulfonyl)phenyl)aniline according to the procedure in Part C of Example 8. The title compound was prepared and purified by the method outlined in Part D of Example 8; mp 110.3° C.; HRMS (M+H)⁺: 533.1265 m/z.

Example 27 3-Trifluoromethyl-1-(2-aminomethyl-4-fluorophenyl)-1H-pyrazole-5-(N-(4-(2-sulfamido-[1,1′]-biphen-4-yl))carboxyamide.TFA

3-Trifluoromethyl-1-(2-azidomethyl-4-fluorophenyl)-1H-pyrazole-5-carboxylic acid was prepared from 3-fluoro-6-aminobenzoic acid by essentially the same method used for 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid in Parts A and B of Example 8. This compound was coupled with 4-((2-N-t-butylsulfonamido)phenyl)aniline according to the procedure in Part C of Example 8. The azidomethyl group was reduced to the aminomethyl group with SnCl₂.2H₂O by the method outlined in Part D of Example 8. The crude reduction product was then refluxed in trifluoroacetic acid (10 mL) for 1 h to remove the t-butyl protecting group. The title compound was isolated by HPLC utilizing gradient elution with a mixture of water:acetonitrile with 0.05% trifluoroacetic acid on a reverse phase C18 (60 Å) column; mp 136.8° C.; HRMS (M+H)⁺: 534.1227 m/z.

Example 28 3-Trifluoromethyl-1-(2-aminomethyl-4-fluorophenyl)-1H-pyrazole-5-(N-(4-(N-((N′-methylsulfonyl)iminoly)pyrrolidino))phenyl)carboxyamide.TFA

Part A: 4-Amino-N-((N′-methylsulfonyl)iminoyl)pyrrolidine 4-Nitrobenzonitrile (5.4 g, 36.5 mmol) in anhydrous methyl acetate (200 mL) and MeOH (20 mL) was cooled to 0° C. and treated with a stream of dry HCl gas for 1 h. The reaction was securely stoppered and left to stand at 5° C. in a refrigerator for 24 h. The solvent was removed and the reaction was evaporated repeatedly (5×) with Et₂O to remove the last traces of free HCl. There was obtained 28.6 g of the imidate as an HCl salt. This material was dissolved in anhydrous MeOH (100 mL) and pyrrolidine (40.1 mmol, 2.85 g) added. The reaction was stirred for 18 h, then evaporated and stirred in 1N HCl (150 mL); the insoluable material was removed by filtration then the HCl solution evaporated. The residue was dried by the azeotropic removal of H₂O with EtOH and there was obtained 7.44 g of the amidine product; LRMS ES⁺ (M+H)⁺: 220.1 m/z.

The free base of the amidine prepared above was formed by suspending the product in 1N NaOH (250 mL) and extracting this suspension with CHCl₃ (3×). The material was dried and evaporated to give 4.49 g of product.

To 3.1 g of the free base of the amidine prepared above (14.2 mmol) in CH₂Cl₂ (100 mL) at 0° C. was added DMAP (2.1 g, 17 mmol) followed by methanesulfonyl chloride (1.95 g, 17 mmol) in CH₂Cl₂ (25 mL). After 18 h at ambient temperature, the reaction was washed with 1N HCl (2×), 1N NaOH and brine, dried and evaporated. There was obtained 3.6 g of the mesylation product; LRMS ES⁺ (M+H)⁺: 298.1.

The mesyltion product (3.6 g, 12 mmol) and SnCl2.2H2O (8.12 g, 36 mmol) in EtOH (100 mL) was heated at reflux for 2 h. The solvent was removed and the residue partioned between 1N NaOH (150 mL) and CH2Cl2 (100 mL). The aqueous layer was extracted with CH2Cl2 (2×100 mL), dried (Na2SO4) and evaporated to give 2.7 g of 4-amino-N-((N′-methylsulfonyl)iminoyl)pyrrolidine; LRMS ES⁺ (M+H)⁺: 268.1 m/z.

Part B: 3-Trifluoromethyl-1-(2-aminomethyl-4-fluorophenyl)-1H-pyrazole-5-(N-(4-(N-((N′-methylsulfonyl)iminoly)pyrrolidino))phenyl)carboxyamide.TFA: 3-Trifluoromethyl-1-(2-azidomethyl-4-fluorophenyl)-1H-pyrazole-5-carboxylic acid was prepared from 3-fluoro-6-aminobenzoic acid by essentially the same method used for 3-trifluoromethyl-1-(2-azidomethyl-4-methoxyphenyl)-1H-pyrazole-5-carboxylic acid in Parts A and B of Example 8. This compound was coupled with 4-amino-N-((N′-methylsulfonyl)iminoyl)pyrrolidine, prepared in Part A of Example 28, according to the procedure in Part C of Example 8. The title compound was prepared and purified by the method outlined in Part D of Example 8; mp 138.4° C.; HRMS (M+H)⁺: 553.1640 m/z.

Example 29 3-Trifluoromethyl-1-(2-(N-glycyl)aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide.TFA

3-Trifluoromethyl-1-(2-(N-glycyl)aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide.TFA: A mixture of 3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide.TFA (prepared in Example 5, 0.15 g, 0.22 mmol), N-Boc glycine (0.039 g, 0.22 mmol) and HBTU (0.084 g, 0.22 mmol) in DMF (3 mL) were cooled to 0° C. and NMM (0.075 g, 0.75 mmol) added. After 6 h, the reaction was diluted with brine and extracted with EtOAc. The EtOAc layer was washed with 5% NaHSO₄ and brine (5×) then dried (MgSO₄) and evaporated to give 0.14 g of product; LRMS ES⁺ (M+H)⁺: 720.4 m/z.

The product from above was stirred in 5% TFA in CH₂Cl₂ (20 mL) for 18 h. The reaction was evaporated and the product purified by HPLC utilizing gradient elution with a mixture of water:acetonitrile with 0.05% trifluoroacetic acid on a reverse phase C18 (60 Å) column to give 0.087 g of the title compound; mp 92.5° C.; HRMS (M+H)⁺: 620.160000 m/z.

Example 30 3-Trifluoromethyl-1-(2-(N-phenylacetyl)aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide

3-Trifluoromethyl-1-(2-(N-phenylacetyl)aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide: A mixture of 3-Trifluoromethyl-1-(2-aminomethyl-4-methoxyphenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide.TFA (prepared in Example 5, 0.15 g, 0.22 mmol) and Et₃N (0.068 g, 0.66 mmol) in CH₂Cl₂ (10 mL) was cooled to 0° C. and phenylacetyl chloride (0.22 mol in 1 mL of CH₂Cl₂) was added dropwise. The reaction was complete in 3 h. It was diluted with more CH₂Cl₂ then washed with 1N HCl, dried and evaporated. The residue was purified further by MPLC on a 200 g column of flash SiO₂ by elution with 1:1 Hexane:EtOAc. Fractions (25 mL) were collected and the product isolated in tubes 44-75. There was obtained 0.086 g of the desired product; mp 179-181° C.; HRMS (M+H)⁺: 681.1786 m/z.

Example 31 3-(Trifluoromethyl)-1-(2-(aminomethyl)phenyl)-1H-pyrazole-5-(N-(2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide.TFA

2-[5-(2-Furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzoic acid: 4,4,4-Trifluoro-1-(2-furyl)-1,3-butanedione (2.4 mL, 16 mmol) was added to 2-hydrazinobenzoic acid (3.01 g, 16 mmol) in acetic acid (20 mL) and heated at reflux for 25 h. The reaction was cooled, diluted with EtOAc, and extracted twice with water. The organic layer was dried over Na₂SO₄, filtered, and evaporated to yield a thick red paste (5.71 g, >100%). ¹H NMR (CDCl₃) δ8.18 (dd, 1H, J=7.7, J′=1.8), 7.74 (td, 1H, J=7.7, J′=1.4), 7.65 (td, 1H, J=7.7, J′=1.5), 7.50 (dd, 1H, J=7.3, J′=1.1), 7.35 (m, 1H), 6.89 (s, 1H), 6.28 (m, 1H), 5.76 (d, 1H, J=3.3).

2-[5-(2-Furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzamide: 2-[5-(2-Furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzoic acid (5.13 g, 16 mmol) was dissolved in thionyl chloride (25 mL) and heated at reflux for 2 h. The excess thionyl chloride was evaporated, and the resulting acid chloride was placed under high vacuum. The acid chloride was then redissolved in CH₂Cl₂ (25 mL) and cooled to 0° C. Conc. aqueous NH₃ (6 mL) was added portionwise over 30 min. The resulting mixture was stirred at 0° C. for 30 min, then at room temperature for 1 h.

The reaction was diluted with water and extracted with CH₂Cl₂ (3×). The organic layers were combined and extracted with 2M Na₂CO₃. The organic layer was dried over MgSO₄, filtered, and evaporated to yield the desired product (4.76 g, 93%). ¹H NMR (CDCl₃) δ7.98 (dd, 1H, J=7.3, J′=2.2), 7.67 (m, 2H), 7.41 (m, 2H), 6.96 (s, 1H), 6.28 (m, 1H), 5.89 (bs, 1H), 5.67 (d, 1H, J=2.9).

2-[5-(2-Furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile: 2-[5-(2-Furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzamide (6.73 g, 21 mmol) and triethylamine (5.8 mL, 42 mmol) were combined in dry CH₂Cl₂ (55 mL) under argon and cooled to 0° C. Trichloroacetyl chloride (2.7 mL, 24 mmol) in CH₂Cl₂ (15 mL) was added dropwise over 30 min. The resulting solution was stirred at 0° C. for 20 min, then at room temperature for 65 min. The reaction was quenched with a small amount of water, then partitioned between 1M HCl and CH₂Cl₂. The organic layer was removed and extracted with sat. NaHCO₃, then dried over Na₂SO₄, filtered, and evaporated to yield crude product (6.66 g). The crude product was chromatographed on silica gel (30-40% EtOAc/hexanes) to yield a yellow solid (6.51 g, >100%). ¹H NMR (CDCl₃) δ7.79 (m, 2H), 7.64 (m, 2H), 7.39 (d, 1H, J=1.8), 6.96 (s, 1H), 6.37 (m, 1H), 6.04 (d, 1H, J=3.7).

2-[5-(2-Furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzylamine: Cobalt chloride (1.76 g, 13.6 mmol) was added to 2-[5-(2-furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile (4.12 g, 13.6 mmol) and sodium borohydride (1.03 g, 27.2 mmol) in DMF (40 mL). The reaction turned black and became warm. An ice bath was added and the reaction was stirred at 0° C. for 45 min, then at room temperature for 23 h. Additional sodium borohydride (0.25 g, 6.6 mmol) was added and the resulting mixture was stirred at room temperature for 6 h. A room temperature water bath was added, and the reaction was quenched with water (10 mL) over 10 min, then MeOH (20 mL), then 6M HCl (20 mL) over 15 min. The quenched reaction was stirred at room temperature for 16 h, diluted with EtOAc, and extracted with water and 0.1M HCl. The resulting emulsion was filtered through celite, and the organic layer was removed, dried over Na₂SO₄, filtered, and evaporated to yield crude product (857 mg). The aqueous layers were combined and neutralized (pH 8) with solid Na₂CO₃ (6.9 g). Addition of EtOAc yielded another emulsion, which was filtered through celite. The organic layer was removed, and the aqueous layer was extracted again with EtOAc. The organic layers were combined, dried over Na₂SO₄, filtered, and evaporated to yield a second batch of crude product (3.55 g). The two batches of crude product were combined and chromatographed on silica gel (0-10% MeOH/CHCl₃) to yield the desired product (3.77 g, 90%). ¹H NMR (CDCl₃) δ7.59 (m, 2H), 7.38 (m, 2H), 7.33 (d, 1H, J=7.3), 6.96 (s, 1H), 6.27 (m, 1H), 5.59 (d, 1H, J=3.6), 3.51 (s, 2H).

t-Butyl 2-[5-(2-furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzylcarbamate: Triethylamine (2.6 mL, 18.7 mmol) and di-t-butyl dicarbonate (4.0 g, 18.4 mmol) were added to 2-[5-(2-furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzylamine (3.77 g, 12.3 mmol) in THF (60 mL) and stirred at room temperature for 17 h. The reaction was concentrated, diluted with Et₂O, and extracted with water (2×). The aqueous layers were combined and extracted with Et₂O. The organic layers were combined, dried over MgSO₄, filtered, and evaporated to yield crude product (5.58 g). The crude product was chromatographed on silica gel (10-20% EtOAc/hexanes) to yield a waxy solid (3.82 g, 76%). ¹H NMR (CDCl₃) δ7.57 (m, 2H), 7.43 (m, 2H), 7.32 (d, 1H, J=7.7), 6.95 (s, 1H), 6.28 (m, 1H), 5.66 (d, 1H, J=3.3), 4.82 (bs, 1H), 4.01 (bd, 2H, J=6.2), 1.39 (s, 9H).

1-(2-([(t-Butoxycarbonyl)amino]methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl-5-carboxylic acid: t-Butyl 2-[5-(2-furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzylcarbamate (3.77 g, 9.2 mmol) was dissolved in t-BuOH (60 mL). A 5% aqueous solution of NaH₂PO₄ (40 mL) was added, followed by portionwise addition of solid KMnO₄ (5.86 g, 37 mmol) over 25 min. The resulting mixture was heated at 65° C. for 40 min. Additional KMnO₄ (1.39 g, 8.8 mmol) was added, and the reaction continued heating at 65° C. for 35 min. The reaction mixture was cooled and filtered through celite, using EtOH and acetone to rinse the celite. The filtrate was concentrated to approx. half its original volume and treated with aq. sodium bisulfite to remove residual KMnO₄. The resulting mixture was extracted with EtOAc, and the organic layer was removed, dried over Na₂SO₄, filtered, and evaporated to yield crude product (1.50 g). The aqueous layer was cooled in ice, acidified with 1M HCl (6 mL) and extracted with EtOAc (containing a small amount of EtOH). Before separating, both layers were filtered through celite and treated with sat NaHCO₃ (1.5 mL). The aqueous layer was removed and extracted twice with EtOAc/EtOH. Solid NaCl was added both times to aid separation of the emulsion. The aqueous layer was extracted with CHCl₃, adjusted to pH 5 with 1M HCl, and extracted twice with CHCl₃/EtOH. The final 6 organic layers were combined, dried over Na₂SO₄, filtered, and evaporated to yield a second batch of product (2.43 g, 68%). The first batch of product was chromatographed on silica gel (0-30% MeOH/CHCl₃) to yield clean product (0.95 g, 27%). ¹H NMR (DMSO) δ7.34 (m, 4H), 7.16 (d, 1H), 6.81 (bs, 1H), 3.79 (bd, 2H), 1.32 (s, 9H).

1-[2-(([(t-Butoxycarbonyl)amino]methyl)phenyl)-5-(2′-methylsufonyl-[1,1′]-biphen-4-yl))aminocarbonyl]-3-(trifluoromethyl)pyrazole: Oxalyl chloride (90 μl, 1.0 mmol) and DMF (2 drops) were added to 1-(2-([(t-butoxycarbonyl)amino]methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl-5-carboxylic acid (200 mg, 0.52 mmol) in CH₂Cl₂ (5 mL) and the resulting solution was stirred for 90 min at room temperature. The solvents were evaporated and the resulting compound was placed briefly under high vacuum before redissolving in CH₂Cl₂ (5 mL). Triethylamine (220 μl, 1.6 mmol), 4-amino-2′-methylsulfonyl-[1,1′]-biphenyl hydrochloride (177 mg, 0.62 mmol), and 4-dimethylaminopyridine (20 mg, 0.16 mmol) were added, and the resulting solution was stirred for 23 h at room temperature. The reaction was extracted with ice-cooled 1M HCl, then sat. NaHCO₃. The organic layer was dried over MgSO₄, filtered, and evaporated to yield crude product (241 mg). The crude product was chromatographed on silica gel (30-40% EtOAc/hexanes) to yield the desired product (64 mg, 20%). ¹H NMR (CDCl₃) δ8.21 (d, 1H, J=8.1), 7.58 (m, 5H), 7.35 (m, 8H), 7.18 (s, 1H), 4.16 (d, 2H, J=5.8), 2.59 (s, 3H), 1.33 (s, 9H).

3-(Trifluoromethyl)-1-(2-(aminomethyl)phenyl)-1H-pyrazole-5-(N-(2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide trifluoroacetic acid salt: TFA (1 mL) was added to 1-[2-(([(t-butoxycarbonyl)amino]methyl)phenyl)-5-(2′-methylsufonyl-[1,1′]-biphen-4-yl))aminocarbonyl]-3-(trifluoromethyl)pyrazole (64 mg, 0.10 mmol) in CH₂Cl₂ (1 mL) and stirred at room temperature for 21 h. The reaction was evaporated and purified by reverse phase prep. HPLC (15-70% MeCN/H₂O/0.5% TFA) to yield the desired product (30 mg, 46%). ¹H NMR (DMSO) d 10.79 (s, 1H), 8.16 (bs, 2H), 8.04 (d, 1H, J=7.7), 7.77 (s, 1H), 7.71 (td, 1H, J=5.8), 7.64 (m, 6H), 7.51 (m, 1H), 7.45 (d, 1H, J=7.6), 7.34 (m, 3H), 3.79 (bm, 2H), 2.78 (s, 3H). ¹⁹F NMR (DMSO) d −61.22, −73.97. HRMS calc. C₂₅H₂₂N₄O₃F₃S: 515.1365; found, 515.1359.

Example 32 3-Trifluoromethyl-1-(2-(aminomethyl)phenyl)-1H-pyrazole-5-(N-(2′-aminosulfonyl-[1,1′]-biphen-4-yl))carboxyamide.TFA

1-[2-(([(t-Butoxycarbonyl)amino]methyl)phenyl)-5-(2′-(t-butylamino)sulfonyl-[1,1′]-biphen-4-yl))aminocarbonyl]-3-(trifluoromethyl)pyrazole: Oxalyl chloride (90 μl, 1.0 mmol) and DMF (2 drops) were added to 1-(2-([(t-butoxycarbonyl)amino]methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl-5-carboxylic acid (Example 31 Part A, 200 mg, 0.52 mmol) in CH₂Cl₂ (5 mL) and the resulting solution was stirred for 95 min at room temperature. The solvents were evaporated and the resulting compound was placed briefly under high vacuum before redissolving in CH₂Cl₂ (5 mL).

Triethylamine (150 μl, 1.1 mmol), 4-amino-2′(t-butylamino)sulfonyl-[1,1′]-biphenyl (190 mg, 0.62 mmol), and 4-dimethylaminopyridine (20 mg, 0.16 mmol) were added, and the resulting solution was stirred for 23 h at room temperature. The reaction was extracted with dilute brine solution, ice-cooled 1M HCl, and sat. NaHCO₃. The organic layer was dried over MgSO₄, filtered, and evaporated to yield crude product (371 mg). The crude product was chromatographed on silica gel (30% EtOAc/hexanes) to yield the desired product (74 mg, 21%). ¹H NMR (CDCl₃) δ8.64 (bs, 1H), 8.15 (dd, 1H, J=7.7, J′=1.5), 7.45 (m, 10H), 7.25 (d, 1H, J=6.9), 7.20 (s, 1H), 5.33 (bs, 1H), 4.15 (d, 2H, J=5.8), 3.49 (bs, 1H), 1.34 (s, 9H), 0.97 (s, 9H).

3-Trifluoromethyl-1-(2-(aminomethyl)phenyl)-1H-pyrazole-5-(N-(2′-aminosulfonyl-[1,1′]-biphen-4-yl))carboxyamide trifluoroacetic acid salt: TFA (2 mL) was added to 1-[2-(([(t-butoxycarbonyl)amino]methyl)phenyl)-5-(2′-(t-butylamino)sulfonyl-[1,1′]-biphen-4-yl))aminocarbonyl]-3-(trifluoromethyl)pyrazole (74 mg, 0.11 mmol) in CH₂Cl₂ (1 mL) and stirred at room temperature for 19 h. Additional TFA (2 mL) was added, and the reaction continued stirring for 3 h. The reaction was evaporated and purified by reverse phase prep. HPLC (15-70% MeCN/H₂O/0.5% TFA) to yield the desired product (41 mg, 59%). ¹H NMR (DMSO) δ10.75 (s, 1H), 8.17 (bs, 3H), 7.98 (dd, 1H, J=7.3), 7.76 (s, 1H), 7.57 (m, 7H), 7.44 (d, 1H, J=6.7), 7.32 (d, 2H, J=8.8), 7.25 (m, 3H) 3.79 (bd, 2H, J=5.1). ¹⁹F NMR (DMSO) δ−61.22, −73.99. HRMS calc. C₂₄H₂₁N₅O₃F₃S: 516.1317; found, 516.1319.

Example 33 3-Trifluoromethyl-1-(2-(aminomethyl)phenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-aminosulfonyl-[1,1′]-biphen-4-yl))carboxyamide.TFA

1-[2-(([(t-Butoxycarbonyl)amino]methyl)phenyl)-5-(3-fluoro-2′-(t-butylamino)sulfonyl-[1,1′]-biphen-4-yl))aminocarbonyl]-3-(trifluoromethyl)pyrazole: Oxalyl chloride (300 μl, 3.4 mmol) and DMF (3 drops) were added to 1-(2-[(t-butoxycarbonyl)amino]methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl-5-carboxylic acid (Example 31 Part A, 888 mg, 2.3 mmol) in CH₂Cl₂ (30 mL) and the resulting solution was stirred for 65 min at room temperature. The solvents were evaporated and the resulting compound was placed briefly under high vacuum before redissolving in CH₂Cl₂ (30 mL). 4-Amino-3-fluoro-2′-(t-butylamino)sulfonyl-[1,1′]-biphenyl (890 mg, 2.8 mmol), and 4-dimethylaminopyridine (420 mg, 3.4 mmol) were added, and the resulting solution was stirred for 22 h at room temperature. The reaction was concentrated and chromatographed on silica gel (20-30% EtOAc/hexanes). The fractions containing product were combined and concentrated to half the original volume, then extracted 3× with ice-cooled 1M HCl, 2× with room temperature 1M HCl, sat. NaHCO₃, 2M HCl, and sat. NaHCO₃. The organic layer was dried over Na₂SO₄, filtered, and evaporated to yield the desired product (600 mg, 38%).

3-Trifluoromethyl-1-(2-(aminomethyl)phenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-aminosulfonyl-[1,1′]-biphen-4-yl))carboxyamide trifluoroacetic acid salt: TFA (9 mL) was added to 1-[2-(([(t-butoxycarbonyl)amino]methyl)phenyl)-5-(3-fluoro-2′-(t-butylamino)sulfonyl-[1,1′]-biphen-4-yl))aminocarbonyl]-3-(trifluoromethyl)pyrazole (600 mg, 0.87 mmol) in CH₂Cl₂ (3 mL) and stirred at room temperature for 18 h. The reaction was evaporated and purified by reverse phase prep. HPLC (10-70% MeCN/H₂O/0.5% TFA) to yield impure product (349 mg). This material was again purified by reverse phase HPLC (5-70% MeCN/H₂O/0.5% TFA) to yield clean product (162 mg, 35%). Any impure fractions containing product were combined and purified by reverse phase HPLC (20-60% MeCN/H₂O/0.5% TFA) to yield additional product (119 mg, 26%) ¹H NMR (DMSO) δ10.62 (s, 1H), 8.16 (bs, 2H), 7.98 (dd, 1H, J=7.0, J′=2.2), 7.79 (s, 1H), 7.54 (m, 7H), 7.39 (s, 2H), 7.28 (m, 2H), 7.15 (d, 1H, J=8.4), 3.78 (bm, 2H). ¹⁹F NMR (DMSO) δ−61.26, −74.29, −122.79. HRMS calc. C₂₄H₂₀N₅O₃F₄S: 534.1223; found, 534.1216.

Example 34 3-Trifluoromethyl-1-(2-(aminomethyl)phenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′′]-biphen-4-yl))carboxyamide.TFA

1-[2-(([(t-Butoxycarbonyl)amino]methyl)phenyl)-5-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))aminocarbonyl]-3-(trifluoromethyl)pyrazole: Oxalyl chloride (320 μ1, 3.7 mmol) and DMF (4 drops) were added to 1-(2-([(t-butoxycarbonyl)amino]methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl-5-carboxylic acid (Example 31 Part A, 940 mg, 2.4 mmol) in CH₂Cl₂ (35 mL) and the resulting solution was stirred for 55 min at room temperature. The solvents were evaporated and the resulting compound was placed briefly under high vacuum before redissolving in CH₂Cl₂ (20 mL). 4-Amino-3-fluoro-2′-methylsulfonyl-[1,1′]-biphenyl (750 mg, 2.8 mmol) in CH₂Cl₂ (15 mL), and 4-dimethylaminopyridine (447 mg, 3.7 mmol) were added, and the resulting solution was stirred for 20 h at room temperature. The reaction was concentrated and chromatographed on silica gel (30-40% EtOAc/hexanes) to yield impure product (802 mg), which was purified on reverse phase prep. HPLC (10-70% MeCN/H2O/0.5% TFA) to yield clean product (645 mg, 42%).

3-Trifluoromethyl-1-(2-(aminomethyl)phenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide trifluoroacetic acid salt: TFA (2 mL) was added to 1-[2-(([(t-butoxycarbonyl)amino]methyl)phenyl)-5-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))aminocarbonyl]-3-(trifluoromethyl)pyrazole (132 mg, 0.21 mmol) in CH₂Cl₂ (2 mL) and stirred at room temperature for 5 h. The reaction was evaporated and purified by reverse phase prep. HPLC (10-70% MeCN/H₂O/0.5% TFA) to yield the desired product (80 mg, 59%). ¹H NMR (DMSO) δ10.65, (s, 1H), 8.16 (bs, 3H), 8.05 (d, 1H, J=6.6), 7.79 (s, 1H), 7.73 (td, 1H, J=6.2, J′=1.5), 7.67 (dd, 1H, J=7.7, J′=1.5), 7.54 (m, 5H), 7.35 (m, 2H), 7.19 (d, 1H, J=8.0), 3.78 (bd, 2H, J=5.5), 2.88 (s, 3H). ¹⁹F NMR (DMSO) δ−61.26, −74.11, −122.19. HRMS calc. C₂₅H₂₁N₄O₃F₄S: 533.1217; found, 533.1258.

Example 35 3-Trifluoromethyl-1-(2-(N-(glycyl)aminomethyl)phenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide.TFA

The title compound was prepared from 1-[2-((aminomethyl)phenyl)-5-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))aminocarbonyl]-3-(trifluoromethyl)pyrazole trifluoroacetic acid salt (prepared in Example 34) and N-Boc glycine according to the procedure in Example 29; HRMS (M+H)⁺: 590.1495 m/z.

Example 36 3-Trifluoromethyl-1-(2-((N-(N-methylglycyl)aminomethyl)phenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′-biphen-4-yl)) carboxyamide.TFA

The title compound was prepared from 1-[2-((aminomethyl)phenyl)-5-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))aminocarbonyl]-3-(trifluoromethyl)pyrazole trifluoroacetic acid salt (prepared in Example 34) and N-Boc-N-methyl glycine according to the procedure in Example 29; HRMS (M+H)⁺: 604.1655 m/z.

Example 37 3-Trifluoromethyl-1-(2-carboxamidophenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide

Methyl 2-[5-(2-furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzoate: 2-[5-(2-furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzoic acid (Example 31 Part A, 26.5 g, 82 mmol) was dissolved in SOCl₂ (130 mL) and heated at reflux for 2.5 h. Excess SOCl₂ was evaporated, and the residual acid chloride was placed under high vacuum. The acid chloride was cooled to 0° C., and dry MeOH (130 mL) was added. The resulting solution was allowed to warm slowly to room temperature, then stirred at room temperature for 22 h. The solvent was evaporated, and the crude product was chromatographed on silica gel (0-30% EtOAc/hexanes) to yield the desired product (22.6 g, 82%). ¹H NMR (CDCl₃) δ8.10 (dd, 1H, J=7.3, J′=1.9), 7.67 (m, 2H), 7.50 (dd, 1H, J=7.7, J′=1.4), 7.37 (s, 1H), 6.92 (s, 1H), 6.29 (m, 1H), 5.77 (d, 1H, J=3.3), 3.62 (s, 3H).

1-(2-Carbomethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-5-carboxylic acid: A 5% aq. solution of NaH₂PO₄ (320 mL) and water (200 mL) were added to methyl 2-[5-(2-furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzoate (23.7 g, 71 mmol) in t-BuOH (470 mL). The reaction was immersed in a room temperature water bath, and solid KMnO₄ (55.8 g, 353 mmol) was added portionwise over 1 h. The reaction was heated at 70° C. for 90 min, cooled, and filtered through celite. The celite was rinsed with acetone and EtOAc. The filtrate was concentrated to remove most of the organics, then extracted with EtOAc. The organic layer was extracted with sat. Na₂SO₃, dried over Na₂SO₄, filtered, evaporated, and set aside. The aqueous layers were combined and neutralized to pH 6.5 with 2M HCl (100 mL), and then extracted with EtOAc (3×). The organic layers were combined, dried over Na₂SO₄, filtered, and evaporated to yield clean product (14.8 g, 67%). ¹H NMR (CDCl₃) δ8.10 (dd, 1H, J=7.3, J′=1.5), 7.64 (m, 2H), 7.42 (dd, 1H, J=7.3, J′=1.1), 7.31 (s, 1H), 3.69 (s, 3H).

1-[2-Carbomethoxyphenyl-5-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))aminocarbonyl]-3-(trifluoromethyl)pyrazole: Oxalyl chloride (2.9 mL, 33 mmol) and DMF (10 drops) were added to 1-(2-carbomethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-5-carboxylic acid (7.0 g, 22 mmol) in dry CH₂Cl₂ (240 mL), and the resulting solution was stirred at room temperature for 80 min. The solvents were evaporated, and the resulting compound was placed briefly under high vacuum before redissolving in CH₂Cl₂ (240 mL). 4-Amino-3-fluoro-2′-methylsulfonyl-[1,1′]-biphenyl hydrochloride (7.4 g, 25 mmol) and 4-dimethylaminopyridine (7.1 g, 58 mmol) were added, and the resulting solution was stirred at room temperature for 67 h. The reaction was extracted with 1M HCl (2×), then sat. NaHCO₃. The organic layer was dried over MgSO₄, filtered, and evaporated to yield crude product. The crude product was chromatographed on silica gel (30-50% EtOAc/hexanes) to yield the desired product (12.4 g, 99%). ¹H NMR (CDCl₃) δ8.29 (t, 1H, J=8.1), 8.21 (m, 2H), 8.11 (dd, 1H, J=7.7, J′=1.5), 7.62 (m, 5H), 7.30 (m, 2H), 7.14 (m, 2H), 3.77 (s, 3H), 2.69 (s, 3H).

1-[2-Carboxyphenyl-5-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))aminocarbonyl]-3-(trifluoromethyl)pyrazole: 1M LiOH (34 mL)was added to 1-[2-carbomethoxyphenyl-S-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))aminocarbonyl]-3-(trifluoromethyl)pyrazole (12.0 g, 21 mmol) in THF (285 mL) and stirred at room temperature for 26 h. Additional 1M LiOH (15 mL) was added, and the reaction continued stirring for 18 h. The resulting solution was heated at 35° C. for 2.5 h, then at 50° C. for 18 h. The reaction was cooled, concentrated, and partitioned between Et₂O and water. The organic layer was extracted again with water (2×). A small amount of white solid was assumed to be product, and was added to the aqueous layer. The aqueous layers were combined, neutralized to pH 7 with 2M HCl (23 mL), and extracted with EtOAc. Additional 2M HCl (2 mL) was added to the aqueous, which was extracted twice with EtOAc. The EtOAc layers were combined, dried over Na₂SO₄, filtered, and evaporated to yield the desired product (10.3 g, 88%). ¹H NMR (CDCl₃) δ8.21 (m, 4H), 7.75 (m, 1H), 7.60 (m, 4H), 7.29 (m, 3H), 7.13 (m, 2H), 2.70 (s, 3H).

3-Trifluoromethyl-1-(2-carboxamidophenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide: 1-[2-Carboxyphenyl-5-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))aminocarbonyl]-3-(trifluoromethyl)pyrazole (3.0 g, 5.5 mmol) was dissolved in SOCl₂ (10 mL) and heated at reflux for 2 h. Excess SOCl₂ was evaporated, and the residual acid chloride was placed under high vacuum. The acid chloride was dissolved in dry CH₂Cl₂ and cooled to 0° C., and conc. aq. NH₃ (2.0 mL) was added over 20 min. The resulting mixture was stirred at room temperature for 18 h. The reaction was diluted with CH₂Cl₂ and extracted with water. The aqueous layer was extracted with CHCl₃, MeOH/CH₂Cl₂, and CH₂Cl₂. All of the organics were combined and extracted with sat. NaHCO₃ (2×), 1M HCl, and sat. NaCl. The organic layer was dried over MgSO₄, filtered, evaporated, and chromatographed on silica gel (30-75% EtOAc/hexanes) to yield the desired product (794 mg, 27%). ¹H NMR (CDCl₃, 400 MHz) δ9.53 (bs, 1H), 8.25 (t, 1H, J=8.3), 8.20 (dd, 1H, J=7.8, J′=1.2), 7.75 (m, 1H), 7.60 (m, 4H), 7.45 (m, 1H), 7.29 (dd, 1H, J=7.6, J′=1.2), 7.20 (dd, 1H, J=11.2, J′=1.9), 7.12 (m, 2H), 6.13 (bs, 1H), 5.68 (bs, 1H), 2.67 (s, 3H).

Example 38 3-Trifluoromethyl-1-(2-cyanophenyl)-1H-pyrazole-5-(N-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))carboxyamide

1-[2-Cyanophenyl-5-(3-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl))aminocarbonyl]-3-(trifluoromethyl)pyrazole: 1-[2-Carboxamidophenyl-5-(3-fluoro-2′1-methylsulfonyl-[1,1′]-biphen-4-yl))aminocarbonyl]-3-(trifluoromethyl)pyrazole (Example 36, 715 mg, 1.3 mmol) and triethylamine (360 μL, 2.6 mmol) were combined in dry CH₂Cl₂ (10 mL) and cooled to 0° C. Trichloroacetyl chloride (160 μl, 1.4 mmol) was added over 5 min. The resulting solution was stirred at 0° C. for 30 min, then at room temperature for 2 h. Additional triethylamine (200 μL, 1.4 mmol) was added, and the reaction continued stirring at room temperature for 68 h. Additional trichloroacetyl chloride (20 μL, 0.2 mmol) was added. After stirring 2 h, the reaction was quenched with water. The organic layer was removed and extracted with 1M HCl and sat. NaHCO₃. A small amount of sat. NaCl was added to break up the emulsion. The organic layer was dried over Na₂SO₄, filtered, evaporated, and chromatographed on silica gel (20-75% EtOAc/hexanes) to yield the desired product (114 mg, 17%). 1H NMR (CDCl₃) δ8.25 (m, 2H), 8.09 (bs, 1H), 7.82 (m, 2H), 7.65 (m, 4H), 7.35 (m, 2H), 7.20 (m, 2H), 2.72 (s, 3H).

Example 39 1-(2′-Aminomethylphenyl)-5-[[(2′-methylsulfonyl)-3-fluoro-[1,1′]-biphen-4-yl]aminocarbonyl]-tetrazole TFA salt

Ethyl 1-(2-cyanophenyl)-5-tetrazole carboxylate: To a solution of anthranilonitrile (10.00 g) and Et₃N (13.21 mL) in CH₂Cl₂ (250 mL) was added ethyloxalyl chloride (9.92 mL) in a dropwise fashion over 30 minutes. The reaction was stirred at RT under N₂ for 3 h. The reaction mixture was filtered. The filtrate was washed with water (2×150 mL) and brine (1×150 mL), filtered through phase separatory paper and evaporated. The residue was dissolved in 60 mL of CH₂Cl₂ and 300 mL of hexane was added. The solution was allowed to stand at RT for the weekend. The precipitate was filtered, rinsed with hexane, and dried under vacuum to give 17.74 g of 1-(2-cyanophenyl)-oxoacetic acid ethyl ester.

A solution of triphenylphosphine (16.83 g) in CCl₄ (100 mL) was stirred at 0° C. for 30 minutes. 1-(2-Cyanophenyl)-oxoacetic acid ethyl ester (7.00 g) in CCl₄ (100 mL) was added and the reaction was stirred at reflux under N₂ for 16 h. The reaction was cooled to RT and the precipitate filtered off. The filtrate was evaporated and dissolved in CH₃CN (300 mL). Sodium azide (2.29 g) was added and the reaction stirred at RT under N₂ for 16 h. The solvent was evaporated and the residue taken up in EtOAc (100 mL). The organic solution was washed with water (2×100 mL) and brine (1×100 mL), dried over MgSO_(4,) and evaporated. The crude material was purified by silica gel chromatography eluting with CH₂Cl₂ to give 3.80 g of the title compound; LRMS (ES⁺) M⁺: 244 m/z.

1-(2′-Aminomethylphenyl)-5-[[(2′-methylsulfonyl)-3-fluoro-[1,1′]-biphen-4-yl]aminocarbonyl]-tetrazole: To a solution of [(2′-methylaminosulfonyl)-3-fluoro-[1,1′]-biphen-4-yl]amine (0.32 g) in anhydrous CH₂Cl₂ (10 mL) was added trimethylaluminum (2.12 mL, 2M in heptane). The reaction was stirred at RT under N₂ for 30 minutes. A solution of ethyl 1-(2-cyanophenyl)-5-tetrazole carboxylate (0.28 g) in anhydrous CH₂Cl₂ (10 mL) was added and the reaction was stirred at RT under N₂ for 64 h. The reaction was quenched with 5 drops of 1N HCl and diluted with CH₂Cl₂ (30 mL). The organic solution was washed with water (2×25 mL) and brine (1×25 mL), filtered through phase separatory paper, and evaporated. The crude material was purified by silica gel chromatography eluting with 10% EtOH/CH₂Cl₂ to give 0.35 g of 1-(2′-cyanophenyl)-5-[[(2′-methylsulfonyl)-3-fluoro-[1,1′]-biphen-4-yl]aminocarbonyl]-tetrazole; LMRS (ES⁻) M⁻: 461 m/z.

Cobalt chloride (0.098 g ) was added to 1-(2′-cyanophenyl)-5-[[(2′-methylsulfonyl)-3-fluoro-[1,1′]-biphen-4-yl]aminocarbonyl]-tetrazole (0.35 g) and sodium borohydride (0.072 g) in DMF (5 mL). The reaction was stirred at room temperature for 16 h. The resulting mixture was stirred at room temperature for 16 h. 6M HCl (5 mL) was added over 5 min. The quenched reaction was stirred at room temperature for 3.5 h, diluted with EtOAc and water. The resulting emulsion was filtered through celite, and the organic layer was washed with 1N HCl, dried over Na₂SO₄, filtered, and evaporated to yield crude product (100 mg). The aqueous layers were combined and neutralized (pH 7) with saturate NaHCO₃, extracted with EtOAc. The organic layers were combined, dried over Na₂SO₄, filtered, and evaporated to yield a second batch of crude product. The two batches of crude product were combined and purified by reverse phase HPLC (10-90% MeCN/H₂O/0.5% TFA) to yield 102 mg of the title compound as its TFA salt. LMRS (ES⁺) M⁺: 467 m/z.

Example 40 1-(2′-Aminomethylphenyl)-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]-tetrazole.TFA

The title compound was prepared in an analogous fashion as its TFA salt. LRMS (ES⁺) M⁺: 468 m/z.

Example 41 1-[2-(Aminomethyl)phenyl]-3-thiomethoxy-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole.TFA

Methyl 3-(thiomethoxy)pyrazole-5-carboxylate: A mixture of methyl 4,4-bis(thiomethoxy)-2-oxo-3-butenoate (9.9 g, 48 mmol) and hydrazine monohydrate (2.6 mL, 53 mmol) in 200 mL of glacial acetic acid was stirred at 100° C. for 18 h. The reaction was cooled and concentrated. The residue was taken up in ethyl acetate, washed with sat'd aq NaHCO₃ and brine, dried (MgSO₄) and concentrated. The solid residue was recrystallized from hexanes/ethyl acetate to afford 6.0 g (73%) of the title compound. ¹H NMR (CDCl₃) δ11.0 (broad s, 1H), 6.74 (s, 1H), 3.88 (s, 3H), 2.48 (s, 3H).

Methyl 1-[2-formylphenyl]-3-(thiomethoxy)pyrazole-5-carboxylate: To a solution of methyl 3-(thiomethoxy)pyrazole-5-carboxylate (0.87 g, 5.05 mmol) in 20 mL of 1,4-dioxane was added 2-formylphenyl boronic acid (1.13 g, 7.58 mmol), pyridine (0.82 mL, 10.1 mmol), crushed 4 A molecular sieves and cupric acetate (1.38 g, 7.58 mmol). The flask was equipped with a drying tube and the mixture was allowed to stir at ambient temperature under an air atmosphere for 18 h. The mixture was filtered through a pad of Celite and concentrated. The residue was purified by flash chromatography to afford 0.22 g (16%) of the title compound. ¹H NMR (CDCl₃) δ9.66 (s, 1H), 8.02 (dd, 1H), 7.69 (td, 1H), 7.63 (t, 1H), 7.42 (d, 1H), 6.96 (s, 1H), 3.75 (s, 3H), 2.55 (s, 3H).

1-[(2-(Hydroxymethyl)phenyl]-3-thiomethoxy-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole: To a solution of methyl 1-[2-formylphenyl]-3-(thiomethoxy)pyrazole-5-carboxylate (0.48 g, 1.74 mmol) in 15 mL of methanol at 0° C. was added sodium borohydride (33 mg, 0.87 mmol). The cooling bath was removed and the reaction was stirred for 10 min and then quenched by dilution with water. The reaction mixture was extracted with ethyl acetate and the organics were washed with brine, dried (MgSO₄) and concentrated to afford 0.41 g (85%) of about a 2:1 mixture of a hydroxy ester and a seven-membered ring lactone. This mixture was used without purification. To a solution of (2-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl)amine hydrochloride (0.89 g, 2.94 mmol) in methylene chloride was added trimethylaluminum (2.95 mL of a 2.0 M solution in hexanes, 5.89 mmol) dropwise. This solution was stirred until gas evolution ceased (15-20 min) and then there was added the hydroxy ester/lactone mixture from above (0.41 g, 1.47 mmol) in methylene chloride. The resulting solution was allowed to stir at reflux for 4 h and then it was cooled and quenched by dropwise addition of sat'd aq ammonium chloride. The mixture was diluted with ethyl acetate, the layers were separated, the organic layer was washed with water and brine, dried (MgSO₄) and concentrated. The solid residue was purified by flash chromatography (elution with 1:1 hexanes/ethyl acetate) to afford 0.68 g (91%) of the title compound. LRMS (ES+): 534.1 (M+Na)⁺.

1-[(2-(Bromomethyl)phenyl]-3-thiomethoxy-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole: To a solution of 1-[(2-(hydroxymethyl)phenyl]-3-thiomethoxy-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole (0.68 g, 1.3 mmol) in 20 mL of methylene chloride was added carbon tetrabromide (1.06 g, 3.2 mmol) and triphenylphosphine (0.84 g, 3.2 mmol). The resulting solution was stirred at ambient temperature for 4 h. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO₄) and concentrated. The residue was purified by flash chromatography (elution with 3:1 hexanes/ethyl acetate) to afford 0.60 g (81%) of the title compound.

1-[(2-(Azidomethyl)phenyl]-3-thiomethoxy-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole: To a solution of 1-[(2-(bromomethyl)phenyl]-3-thiomethoxy-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole (0.42 g, 0.73 mmol) in 5 mL of N,N-dimethylformamide was added sodium azide (0.38 g, 5.85 mmol). This mixture was stirred at ambient temperature for 1 h and then was diluted with ethyl acetate. The organics were washed with water and brine, dried (MgSO₄) and concentrated to afford 0.38 g (97%) of the title compound which was used directly without purification. LRMS (ES⁺): 559.1 (M+Na)⁺.

1-[2-(Aminomethyl)phenyl]-3-thiomethoxy-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole, trifluoroacetic acid salt: To a solution of 1-[(2-(azidomethyl)phenyl]-3-thiomethoxy-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole (0.38 g, 0.71 mmol) in 10 mL of methanol was added tin (II) chloride (0.80 g, 4.24 mmol). The reaction mixture was stirred at reflux for 1 h and then was cooled to room temperature and diluted with ethyl acetate. The organics were washed with 5% aq sodium hydroxide and brine, dried (MgSO₄) and concentrated. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a H₂O/CH₃CN gradient with 0.5% TFA) and lyophilized to afford 230 mg (52%) of the title compound as a white powder. LRMS (ES+): 511.1 (M+H)⁺.

Example 42 1-[2-(aminomethyl)phenyl]-3-methysulfonyl-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole.TFA

1-[(2-(Bromomethyl)phenyl]-3-methylsulfonyl-5-[(2-fluoro)-(2′-methylsulfonyl-(1,1′]-biphen-4-yl)aminocarbonyl]pyrazole: To a solution of 1-[(2-(bromomethyl)phenyl]-3-thiomethoxy-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole (85 mg, 0.15 mmol) in 10 mL of methylene chloride was added m-chloroperoxybenzoic acid (130 mg of 57-86% pure material, ˜0.5 mmol). The resulting solution was stirred at ambient temperature for 3 h. The reaction was diluted with ethyl acetate, washed with sat'd aq NaHCO₃ and brine, dried (MgSO₄) and concentrated to afford 80 mg (88%) of the title compound which was sufficiently pure to be used without purification.

1-[(2-(Azidomethyl)phenyl]-3-methylsulfonyl-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole: To a solution of 1-[(2-(bromomethyl)phenyl]-3-methylsulfonyl-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole (55 mg, 0.09 mmol) in 1 mL of dimethylsulfoxide was added sodium azide (30 mg, 0.45 mmol). This mixture was stirred at ambient temperature for 1 h and then was diluted with ethyl acetate. The organics were washed with water and brine, dried (MgSO₄) and concentrated to afford 50 mg (97%) of the title compound which was used directly without purification. LRMS (ES+): 591.1 (M+Na)⁺.

1-[2-(Aminomethyl)phenyl]-3-methylsulfonyl-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole, trifluoroacetic acid salt: To a solution of 1-[(2-(azidomethyl)phenyl]-3-methylsulfonyl-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole (90 mg, 0.16 mmol) in 4 mL of methanol was added tin (II) chloride (0.30 g, 1.6 mmol). The reaction mixture was stirred at reflux for 1 h and then was cooled to room temperature and diluted with ethyl acetate. The organics were washed with 5% aq sodium hydroxide and brine, dried (MgSO₄) and concentrated. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a H₂O/CH₃CN gradient with 0.5% TFA) and lyophilized to afford 18 mg (17%) of the title compound as a white powder. LRMS (ES+): 543.2 (M+H)⁺.

Example 43 1-[2-(aminomethyl)phenyl]-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]triazole.TFA

2-Azidobenzyl alcohol: To a solution of 2-aminobenzyl alcohol (12.0 g, 97.4 mmol) in 50 mL of trifluoroacetic acid at 0° C. was added sodium nitrite (7.39 g, 107.2 mmol). This solution was stirred for 45 min and then there was added sodium azide (6.33 g, 97.4 mmol) dropwise as a solution in water. The resulting mixture was stirred at 0° C. for 45 min and then was carefully quenched by slow addition of potassium carbonate. The reaction mixture was diluted with ethyl acetate, washed with brine, dried (MgSO₄), filtered through a pad of silica gel and concentrated to afford 10.5 g (72%) of the title compound which was used without further purification. ¹H NMR (CDCl₃) δ7.33 (m, 2H), 7.14 (m, 2H), 4.59 (s, 2H), 2.69 (broad s, 1H).

(2-Azidophenyl)methyl propiolate: To a solution of 2-azidobenzyl alcohol (15.66 g, 105.1 mmol) in 200 mL of methylene chloride was added propiolic acid (7.1 mL, 115.6 mmol), dicyclohexylcarbodiimide (20.0 g, 110.3 mmol) and 4-dimethylaminopyridine (1.93 g, 15.8 mmol). The resulting mixture was allowed to stir at ambient temperature for 18h. The mixture was filtered, concentrated and the residue was purified by flash chromatography (elution with 1:1 hexanes/ethyl acetate) to afford 10.7 g (51%) of the title compound. H NMR (CDCl₃) δ7.40 (m, 2H), 7.17 (m, 2H), 5.20 (s, 2H), 2.92 (s, 1H).

Triazololactone: A solution of (2-azidophenyl)methyl propiolate (10.7 g, 53.2 mmol) in 100 mL of toluene was stirred at 100° C. for 18 h. The reaction was cooled and concentrated and the residue was purified by flash chromatography (elution with 1:1 hexanes/ethyl acetate) to afford 1.4 g (13%) of the title compound. ¹H NMR (CDCl₃) δ8.38 (s, 1H), 8.04 (d, 1H), 7.63 (m, 1H), 7.54 (m, 2H), 5.16 (s, 2H).

1-[(2-(Hydroxymethyl)phenyl]-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]triazole: To a solution of (2-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl)amine hydrochloride (2.10 g, 6.96 mmol) in methylene chloride was added trimethylaluminum (20.8 mL of a 2.0 M solution in hexanes, 41.8 mmol) dropwise. This solution was stirred until gas evolution ceased (about 30 min) and then there was added the triazololactone from above (1.40 g, 6.96 mmol) as a solution in methylene chloride. The resulting solution was allowed to stir at reflux for 18 h and then it was cooled and quenched by dropwise addition of sat'd aq ammonium chloride. The mixture was diluted with ethyl acetate, the layers were separated, the organic layer was washed with water and brine, dried (MgSO₄) and concentrated. The solid residue was purified by flash chromatography (elution with 3:1 ethyl acetate/hexanes) to afford 1.0 g (31%) of the title compound. LRMS (ES+): 467.2 (M+H)⁺.

1-[(2-(Bromomethyl)phenyl]-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]triazole: To a solution of 1-[(2-(hydroxymethyl)phenyl]-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]triazole (0.80 g, 1.71 mmol) in 20 mL of methylene chloride was added carbon tetrabromide (2.83 g, 8.55 mmol) and triphenylphosphine (2.24 g, 8.55 mmol). The resulting solution was stirred at ambient temperature for 18 h. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO₄) and concentrated. The residue was purified by flash chromatography (elution with 1:1 hexanes/ethyl acetate) to afford 0.80 g (89%) of the title compound. LRMS (ES+): 529.1/531.1 (M+H)⁺.

1-[(2-(Azidomethyl)phenyl]-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]triazole: To a solution of 1-[(2-(bromomethyl)phenyl]-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]triazole (0.25 g, 0.47 mmol) in 10 mL of N,N-dimethylformamide was added sodium azide (0.37 g, 5.6 mmol). This mixture was stirred at 65° C. for 18 h and then was cooled and diluted with ethyl acetate. The organics were washed with water and brine, dried (MgSO₄) and concentrated to afford 0.22 g (96%) of the title compound which was used directly without purification. LRMS (ES+): 514.2 (M+Na)⁺.

1-[2-(Aminomethyl)phenyl]-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]triazole, trifluoroacetic acid salt: To a solution of 1-[(2-(azidomethyl)phenyl]-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]triazole (0.22 g, 0.45 mmol) in 10 mL of absolute ethanol was added 10% palladium on carbon catalyst (25 mg) and concentrated HCl (0.04 mL, 0.45 mmol). The reaction mixture was stirred at ambient temperature under 1 atm of hydrogen for 2 h and then was filtered through a pad of Celite and concentrated. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a H₂O/CH₃CN gradient with 0.5% TFA) and lyophilized to afford 26 mg (10%) of the title compound as a white powder. LRMS (ES+): 466.2 (M+H)⁺.

Example 44 1-[2-(Aminomethyl)phenyl]-5-[(2-fluoro)-(2′-methylsulfonyl)-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole.TFA

Methyl 1-[2-methylphenyl]pyrazole-5-carboxylate: A neat mixture of methyl pyruvate (11.37 mL, 125.9 mmol) and dimethylformamide dimethylacetal (16.72 mL, 125.9 mmol) was stirred at 80° C. for 24 h. The mixture was cooled and concentrated. A portion of the residue (4.00 g, 25.45 mmol) was dissolved in 50 mL of glacial acetic acid and then there was added o-tolylhydrazine hydrochloride (4.44 g, 27.99 mmol). This mixture was stirred at 100° C. for 18 h and then was cooled and concentrated. The residue was dissolved in ethyl acetate, washed with sat'd aq sodium carbonate and brine, dried (MgSO₄) and concentrated. The residue was purified by flash chromatography (elution with 2:1 hexanes/ethyl acetate) to afford 3.0 g (55%) of the title compound. ¹H NMR (CDCl₃) δ7.70 (d, 1H), 7.4-7.2 (m, 4H), 7.00 (d, 1H), 3.71 (s, 3H), 2.00 (s, 3H).

Methyl 1-[2-(bromomethyl)phenyl]pyrazole-5-carboxylate: To a solution of methyl 1-[2-methylphenyl]pyrazole-5-carboxylate (1.00 g, 4.62 mmol) in 20 mL of carbon tetrachloride was added N-bromosuccinimide (0.823 g, 4.62 mmol) and AIBN (76 mg, 0.46 mmol). This mixture was stirred at 80° C. for 18 h. The volatiles were removed and the residue was taken up in ether, filtered through a pad of silica gel and concentrated to afford 1.3 g (95%) of the title compound which was used without further purification. LRMS (ES+): 295.0/297.0 (M+H)⁺.

Methyl 1-[2-(azidomethyl)phenyl]pyrazole-5-carboxylate: To a solution of methyl 1-[2-(bromomethyl)phenyl]pyrazole-5-carboxylate (1.30 g, 4.40 mmol) in 10 mL of N,N-dimethylformamide was added sodium azide (2.86 g, 44.0 mmol). This mixture was stirred at ambient temperature for 48 h and then was diluted with ethyl acetate. The organics were washed with water and brine, dried (MgSO₄) and concentrated to afford 0.80 g (71%) of the title compound which was used directly without purification. LRMS (ES+): 280.1 (M+Na)⁺.

1-[(2-(Azidomethyl)phenyl]-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole: To a solution of (2-fluoro-2′-methylsulfonyl-[1,1′]-biphen-4-yl)amine hydrochloride (0.94 g, 3.11 mmol) in 20 mL of methylene chloride was added trimethylaluminum (4.67 mL of a 2.0 M solution in hexanes, 9.33 mmol) dropwise. This solution was stirred until gas evolution ceased (about 30 min) and then there was methyl 1-[2-(azidomethyl)phenyl]pyrazole-5-carboxylate (0.80 g, 3.11 mmol) as a solution in methylene chloride. The resulting solution was allowed to stir at reflux for 18 h and then it was cooled and quenched by dropwise addition of sat'd aq ammonium chloride. The mixture was diluted with ethyl acetate, the layers were separated, the organic layer was washed with water and brine, dried (MgSO₄), filtered through a pad of silica gel and concentrated to afford 1.0 g (67%) of the title compound. LRMS (ES+): 513.0 (M+Na)⁺.

1-[2-(Aminomethyl)phenyl]-5-[(2-fluoro)-(2-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole, trifluoroacetic acid salt: To a solution of 1-[(2-(azidomethyl)phenyl]-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1]-biphen-4-yl)aminocarbonyl]pyrazole (0.50 g, 1.0 mmol) in 20 mL of absolute ethanol was added 10% palladium on carbon catalyst (50 mg) and concentrated HCl (0.085 mL, 1.0 mmol). The reaction mixture was stirred at ambient temperature under 1 atm of hydrogen for 2 h and then was filtered through a pad of Celite and concentrated. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a H₂O/CH₃CN gradient with 0.5% TFA) and lyophilized to afford 60 mg (10%) of the title compound as a white powder. LRMS (ES+): 465.2 (M+H)⁺.

Example 45 1-[2-(Aminomethyl)phenyl]-3-trifluoromethyl-5-[((2-fluoro)-(2′-pyrrolidinomethyl)-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole.TFA

Part A: 2-Fluoro-4-((2′-tert-butyldimethylsilyloxymethyl)phenyl)aniline: A solution of 2-formylphenylboronic acid (5 g, 33.3 mmol) and 4-bromo-2-fluoroaniline (4.2 g, 22.2 mmol) in THF (80 mL) and aqueous Na₂CO₃ solution (2M, 80 mL) was bubbled with nitrogen for 10 minutes. After Pd(PPh₃)₄ (1.54 g, 1.33 mmol) was added, the resulting mixture was refluxed under nitrogen for 4 hours. The THF layer was separated and filtered through a pad of silica gel. The silica gel was washed with THF. To the combined filtrates containing 2-fluoro-4-(2′-formylphenyl)aniline (65 mL) was portion by portion added NaBH₄ (2.2 g, 29.1 mmoL). The resulting mixture was stirred at room temperature for 1 hour, quenched with 1N HCl (10 mL), and washed with 1N HCl (100 mL×3). The combined HCl layers were neutralized with 50% NaOH to pH 12 and extracted with EtOAc (100 mL×3). The EtOAc layers were dried over Na₂SO₄, concentrated, and purified by column chromatography with a graduate solvent (hexane to EtOAc) to give 2-fluoro-4-(2′-hydroxymethylphenyl)aniline (3.83 g, 97.6%). ¹H NMR (CDCl₃) δ7.53 (dd, J=6.6 Hz, J=2.2 Hz, 1H), 7.36-7.33 (m, 2H), 7.25 (dd, J=6.6 Hz, J=2.2 Hz, 1H), 7.06 (dd, J=12.1 Hz, J=1.8 Hz, 1H), 6.97 (dd, J=8.0 Hz, J=1.8 Hz, 1H), 6.82 (t, J=8.8 Hz, 1H), 4.63 (s, 2H), 3.79 (bs, 2H); ¹⁹F NMR (CDCl₃): δ−135.66 (dd, J=12.21 Hz, J=9.2 Hz); CIMS(CI) m/z 218 (M+H, 100%).

To a solution of 2-fluoro-4-(2′-hydroxymethyl-phenyl)aniline (5 g, 23 mmol) in THF (150 mL) was added imidazole (2.35 g, 34.5 mmol) and 2′-tert-butyldimethylsilylchloride (5.18 g, 34.5 mmol), and the resulting mixture was stirred at room temperature for 24 hours. The mixture was diluted with hexane (150 mL) and washed with water (150 mL). The organic layer was washed with brine, dried over MgSO_(4,) purified by column chromatography with hexane and methylenechloride (1 to 1) to give 2-fluoro-4-((2′-tert-butyldimethylsilyloxymethyl)phenyl)aniline (7.1 g, 92.8%) as a colorless oil. ¹H NMR (CDCl₃) δ7.55 (dd, J=7.7 Hz, J=1.1 Hz, 1H), 7.35 (dd, J=7.4 Hz, J=1.9 Hz, 1H), 7.30 (dd, J=9.1 Hz, J=1.4 Hz, 1H), 7.20 (dd, J=7.3 Hz, J=1.5 Hz, 1H), 7.05 (dd, J=12.1 Hz, J=1.8 Hz, 1H), 6.93 (dd, J=8.0 Hz, J=1.4 Hz, 1H), 6.80 (dd, J=9.1 Hz, J=8.0 Hz, 1H), 4.60 (s 2H), 3.77 (bs, 2H), 0.91 (s, 9H), 0.04 (s, 6H); ¹⁹F NMR (CDCl₃): δ−136.04; CIMS: 332 (M+H, 100).

Part B: 1-(2-cyanophenyl)-5-furyl-3-trifluoromethylpyrazole: To a solution of 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione (2.06 g, 10 mmol) in ethanol (mL) was added hydrazine monohydrate (0.46 g, 10 mmol). The resulting mixture was refluxed for 16 hours and dried under vacuum to give 5-furyl-3-trifluoromethyl-3-hydroxypyrazoline in almost quantitative yield. ¹H NMR (CDCl₃) δ7.48 (d, J=1.9 Hz, 1H), 6.63 (d, J=3.7 Hz, 1H), 6.47 (dd, J=3.7 Hz, J=1.9 Hz, 1H), 6.16 (s, 1H), 3.48 (d, J=17.9 Hz, 1H), 3.18 (d, J=17.9 Hz, 1H); ¹⁹F NMR (CDCl₃): δ−81.47; ESMS(+): 221 (M+H, 100).

To a solution of 2-fluorobenzonitrile (0.605 g, 5 mmol) and 5-furyl-3-trifluoromethyl-3-hydroxypyrazoline (1.1 g, 5 mmol) in DMF (10 mL) was added Cs₂CO₃ (1.63 g, 5 mmol), and the resulting mixture was stirred at 110° C. for 16 hours. The mixture was diluted with EtOAc, washed with brine (×5), dried over MgSO₄, and purified by column chromatography with a gradient solvent (hexane to ethyl acetate) to give 1-(2-cyanophenyl)-5-furyl-3-trifluoromethylpyrazole and 1-(2-cyanophenyl)-3-furyl-5-trifluoromethylpyrazole (1.27 g, 83.8%) in a ratio of 95 to 5. ¹H NMR (CDCl₃) δ7.82 (dd, J=7.7 Hz, J=1.5 Hz, 1H), 7.77 (dd, J=7.7 Hz, J=1.5 Hz, 1H), 7.66 (td, J=7.7 Hz, J=1.1 Hz, 1H), 7.61 (d, J=7.7 Hz, 1H), 7.39 (d, J=1.4 Hz, 1H), 6.96 (s, 1H), 6.37 (dd, J=3.3 Hz, J=1.4 Hz, 1H), 6.04 (d, J=3.3 Hz, 1H); ¹⁹F NMR (CDCl₃): δ−62.98; ESMS(+): 304 (M+H, 100).

Part C: 1-(2-(N-Boc-aminomethyl)phenyl)-3-trifluoromethylpyrazol-5-yl-carboxylic acid: To a solution of 1-(2-cyanophenyl)-5-furyl-3-trifluoromethylpyrazole (1.5 g, 4.67 mmol) in DMF (20 mL) was portion by portion added NaBH₄ (0.71 g, 18.7 mmol) and then CoCl₂ (0.61 g, 4,67 mmol) at 0° C. After the resulting mixture was stirred at room temperature for 18 hours, a black suspension was cooled to 0° C. and carefully acidified with 6N HCl (20 mL). The resulting mixture was stirred at room temperature for 3 hours, and neutralized with 1N NaOH to pH 14. The mixture was diluted with EtOAc (100 mL), and filtered through a pad of sand (top layer) and Celite (bottom layer). The filtrate was separated and the organic layer was washed with brine (5×10 mL), dried over Na₂SO_(4,) and concentrated to give 1-(2-(aminomethyl)phenyl)-5-furyl-3-trifluoromethylpyrazole (1.4 g, 91.5%). ¹H NMR (CD₃OD) δ7.69-7.61 (m, 2H), 7.52 (d, J=1.5 Hz, 1H), 7 47 (td, J=7.7 Hz, J=1.1 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.07 (s, 1H), 6.34 (dd, J=1.8 Hz, J=3.6 Hz, 1H), 5.75 (d, J=3.3 Hz, 1H), 3.40 (s, 2H); ESMS(+): 308 (M+H, 100);

To a solution of 1-(2-(aminomethyl)phenyl)-5-furyl-3-trifluoromethylpyrazole (1.4 g, 4.27 mmol) in THF (10 mL) was added a solution of (Boc)₂O (1.4 g, 6.4 mmol) in THF (10 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc (100 mL), washed with water and brine, dried over Na₂SO_(4,) and concentrated to provide crude 1-(2-(N-Boc-aminomethyl)phenyl)-5-furyl-3-trifluoromethylpyrazole. ¹H NMR (CDCl₃) δ7.60-7.55 (m, 2H), 7.42 (d, J=6.2 Hz, 1H), 7 40 (s, 1H), 7.32 (d, J=7.7 Hz, 1H), 6.95 (s, 1H), 6.28 (dd, J=1.8 Hz, J=3.3 Hz, 1H), 5.65 (d, J=3.3 Hz, 1H), 4.01 (d, J=6.8 Hz, 2H), 3.40 (s, 2H), 1.41 (s, 9H); ¹⁹F NMR (CDCl₃): δ−62.76.

To a solution of crude product in acetone (20 mL) and water (20 mL) was portion by portion added KMnO₄ (3.95 g, 25 mmol), and the resulting mixture was stirred at 60° C. for 20 minutes and then filtered through Celite. The filtrate was concentrated, acidified with 1N HCl to pH 4, and extracted with EtOAc (3×50 mL). The organic layer was washed with brine, dried over Na₂SO₄, concentrated, and purified by column chromatography with 20% MeOH in dichloromethane to provide 1-(2-(N-Boc-aminomethyl)phenyl)-3-trifluoromethylpyrazol-5-yl-carboxylic acid (1.05 g, 56% for the two steps). ESMS(−): 384.2 (M−H, 100).

Part D: 1-(2-(N-Boc-aminomethyl)phenyl)-3-trifluoromethyl-5-[((2-fluoro)-(2′-hydroxymethylsilyloxymethyl)-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole: To a solution of 1-(2-(N-Boc-aminomethyl)phenyl)-3-trifluoromethylpyrazol-5-yl-carboxylic acid (0.768 g, 2 mmol) in CH₂Cl₂ (50 mL) was added DMF (1 drop) and oxalyl chloride (0.381 g, 3 mmol), and the resulting mixture was stirred at room temperature for 1.5 hours. The mixture was concentrated and the residue was dissolved in THF (10 mL). To the solution was added a solution of 2-fluoro-4-(2′-(tert-butyldimethylsilyloxymethyl)phenyl)aniline (0.6 g, 1.8 mmoL) in THF (10 mL) and Et₃N (1.5 mL), and the resulting mixture was stirred at room temperature for 24 hours. The mixture was diluted with EtOAc (100 mL), washed with water and brine, dried over MgSO₄, and purified on thin layer chromatography with CH₂Cl₂/hexane (3:2) to give 1-(2-(N-Boc-aminomethyl)phenyl)-3-trifluoromethyl-5-[((2-fluoro)-(2′-tert-butyldimethylsilyloxymethyl)-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole (0.49 g, 80%).

To a solution of 1-(2′-N-Boc-aminomethylphenyl)-3-trifluoromethyl-5-[((2-fluoro)-(2′-tert-butyldimethylsilyloxymethyl]-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole (0.57 g, 0.93 mmol) in THF (10 mL) was added Bu₄NF (1M in THF, 3 mL), and the resulting solution was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc (150 mL), washed with water (20 mL), dried over Na₂SO₄, and purified by column chromatography with a gradient solvent (hexane to EtOAc) to give 1-(2-(N-Boc-aminomethyl)phenyl)-3-trifluoromethyl-5-[((2-fluoro)-(2′-hydroxymethyl)-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole (484 mg, ˜100%). ¹H NMR (CD₃OD) δ7.69 (t, J=8.0 Hz, 1H), 7.55-7.27 (m, 9H), 7.21 (dd, J=7.4 Hz, J=1.8 Hz, 1H), 7.13 (dd, J=8.4 Hz, J=1.1 Hz, 1H), 4.46 (s, 2H), 4.05 (s, 2H), 1.34 (s, 9H); ¹⁹F NMR (CD₃OD): δ−64.08, −125.53; ESMS(+): 606.3 (M+Na, 100).

Part E: 1-(2-(aminomethyl)phenyl)-3-trifluoromethyl-5-[((2-fluoro)-(2′-pyrrolidinomethyl)-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole, TFA salt: To a solution of 1-(2-(N-Boc-aminomethyl)phenyl)-3-trifluoromethyl-5-[((2-fluoro)-(2′-hydroxymethyl)-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole (150 mg, 0.26 mmol) in THF (5 mL) was added Cs₂CO₃ (167 mg, 0.51 mmol) and MsCl (4 mg, 0.39 mmol). After the resulting mixture was stirred at room temperature for 18 hours and concentrated, the residue was dissolved in THF (10 mL) and treated with pyrrolidine (0.5 mL) at room temperature 8 hours. ESMS(+): 638.4 (M+H, 100). The mixture was treated with TFA/CH₂Cl₂ (1 to 1, 10 mL) at room temperature for 5 hours, and concentrated. The residue was purified on HPLC with a gradient solvent (H₂O—CH₃CN-0.05% TFA) on C18 give the title compound (50 mg, 36% for the two steps). ¹H NMR (CD₃OD) δ7.80 (T, J=8.1 HZ, 1H), 7.71-7.30 (m. 9H), 7.27 (dd, J=11.3 Hz, J=1.8 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 4.40 (s, 2H), 3.99 (s, 2H), 3.42-3.34 (m, 2H), 2.93-2.87 (m, 2H), 2.00-1.94 (m, 4H); ¹⁹F NMR (CD₃OD): δ−64.22, −77.57(TFA), −123.82; HRMS: 538.2243 for C₂₉H₂₈O₁F₄N₅.

Example 46 1-[2-(Aminomethyl)phenyl]-3-trifluoromethyl-5-[((2-fluoro)-(2′-hydroxymethyl)-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole.TFA

A solution of 1-(2-(N-Boc-aminomethyl)phenyl)-3-trifluoromethyl-5-[((2-fluoro)-(2′-hydroxymethylsilyloxymethyl)-[1,1′]-biphen-4-yl)aminocarbonyl]pyrazole (10 mg) was treated with TFA/CH₂Cl₂ (1 to 1, 1 mL) at room temperature for 3 hours and concentrated. The residue was purified by HPLC with a gradient solvent (H₂O—CH₃CN-0.05% TFA) on C18 to give the title compound (2 mg). ¹H NMR (CD₃OD): δ7.66-7.45 (m, 6H), 7.38-7.21 (m, 4H), 7.15 (d, J=9.5 Hz, 1H), 7,10 (d, J=6.6 Hz, 1H), 4.39 (s, 2H), 3.91 (s, 2H); ¹⁹F NMR (CD₃OD): δ−64.23, −77.38, −125.40; ESMS(−): 483.2 (M−H, 100).

TABLE 1

Unless otherwise indicated, D is at the 2-position and is CH₂NH₂. Ex M A-B MS 1 pyrazole-b 2′-H₂NSO₂-biphenyl 492.2 (R = 4-OCH₃) 2 pyrazole-c 2′-H₂NSO₂-biphenyl 492.2 (R = 4-OCH₃) 3 pyrazole-b 2′-(CH₃)HNSO₂-biphenyl 512 (D = CH₂N(Me)₂) (R = 4-OCH₃) 4 pyrazole-a 3-F-2′-H₂NSO₂-biphenyl 528.1 (R = 4-OCH₃) 5 pyrazole-a 3-F-2′-CH₃SO₂-biphenyl 378.2 (R = 4-OCH₃) 6 pyrazole-a 2′-CH₃SO₂-biphenyl 545.1 (R = 4-OCH₃) 7 pyrazole-a 2′-H₂NSO₂-biphenyl 546.2 (R = 4-OCH₃) 8 pyrazole-a 4-(N-pyrrolidino-carbonyl)phenyl 488.2 (R = 4-OCH₃) 9 pyrazole-a phenylmethylsulfonyl-piperidin-4-yl 552.2 (R = 4-OCH₃) 10 pyrazole-a 5-(2-H₂NSO₂-phenyl)pyrid-2-yl 547.1 (R = 4-OCH₃) 11 pyrazole-a 5-(2-pyridyl)pyrid-2-yl 469.2 (R = 4-OCH₃) 12 pyrazole-a benzylpiperidin-4-yl 488.2 (R = 4-OCH₃) 13 pyrazole-a phenylsulfonylpiperidin-4-yl 538.2 (R = 4-OCH₃) 14 pyrazole-a 3-F-2′-CH₃SO₂-biphenyl 567.1 (R = 4-Cl) 15 pyrazole-a 3-F-2′-H₂NSO₂-biphenyl 568.1 (R = 4-Cl) 16 pyrazole-a 3-F-2′-CH₃SO₂-biphenyl 567.1 (R = 5-Cl) 17 pyrazole-a 3-F-2′-H₂NSO₂-biphenyl 568.1 (R = 5-Cl) 18 pyrazole-a 3-F-2′-CH₃SO₂-biphenyl 551.1 (R = 4-F) 19 pyrazole-a 3-F-2′-H₂NSO₂-biphenyl 552.1 (R = 4-F) 20 pyrazole-a 3-F-2′-CH₃SO₂-biphenyl 551.1 (R = 5-F) 21 pyrazole-a 3-F-2′-H₂NSO₂-biphenyl 552.1 (R = 5-F) 22 pyrazole-a 3-F-2′-CH₃SO₂-biphenyl 569.1 (R = 4, 5-F) 23 pyrazole-a 3-F-2′-H₂NSO₂-biphenyl 570.1 (R = 4, 5-F) 24 pyrazole-a 3-F-2′-CH₃SO2-biphenyl 551.1 (R = 3-F) 25 pyrazole-a 3-F-2′-H₂NSO₂-biphenyl 552.1 (R = 3-F) 26 pyrazole-a 2′-CH₃SO₂-biphenyl 533.1 (R = 4-F) 27 pyrazole-a 2′-H₂NSO₂-biphenyl 534.1 (R = 4-F) 28 pyrazole-a 4-(N-pyrrolidino-CH₃SO₂- 553.2 (R = 4-F) iminolyl)phenyl 29 pyrazole-a 3-F-2′-CH₃SO₂-biphenyl 620.2 (D = N-glycyl-NH₂CH₂) (R = 4-OCH₃) 30 pyrazole-a 3-F-2′-CH₃SO₂-biphenyl 681.2 (D = C₆H₅CH₂C(O)—NH₂CH₂) (R = 4-OCH₃) 31 pyrazole-a 2′-CH₃SO₂-biphenyl 515.1 32 pyrazole-a 2′-H₂NSO₂-biphenyl 516.1 33 pyrazole-a 3-F-2′-H₂NSO₂-biphenyl 534.1 34 pyrazole-a 3-F-2′-CH₃SO₂-biphenyl 533.1 35 pyrazole-a 3-F-2′-CH₃SO₂-biphenyl 590.1 (D = glycyl-NH₂CH₂) 36 pyrazole-a 3-F-2′-CH₃SO₂-biphenyl 604.2 (D = N—CH₃-glycyl-NH₂CH₂) 37 pyrazole-a 3-F-2′-CH₃SO₂-biphenyl (D = CONH₂) 38 pyrazole-a 3-F-2′-CH₃SO₂-biphenyl (D = CN) 39 tetrazole 3-F-2′-CH₃SO₂-biphenyl 467 40 tetrazole 3-F-2′-H₂NSO₂-biphenyl 468 41 pyrazole-d 3-F-2′-CH₃SO₂-biphenyl 511.1 42 pyrazole-e 3-F-2′-CH₃SO₂-biphenyl 543.2 43 triazole 3-F-2′-CH₃SO₂-biphenyl 466.2 44 pyrazole-f 3-F-2′-CH₃SO₂-biphenyl 465.2

The following tables contain representative examples of the present invention. Each entry in each table is intended to be paired with each formulae at the start of the table. For example, in Table 2, example 1 is intended to be paired with each of formulae a-bbbb and in Table 3, example 1 is intended to be paired with each of formulae a-bbbb.

The following groups are intended for group A in the following tables.

TABLE 2

Ex # R^(1a) A B 1 CH₃ phenyl 2-(aminosulfonyl)phenyl 2 CH₃ phenyl 2-(methylaminosulfonyl)phenyl) 3 CH₃ phenyl 1-pyrrolidinocarbonyl 4 CH₃ phenyl 2-(methylsulfonyl)phenyl 5 CH₃ phenyl 4-morpholino 6 CH₃ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 7 CH₃ phenyl 4-morpholinocarbonyl 8 CH₃ phenyl 2-methyl-1-imidazolyl 9 CH₃ phenyl 5-methyl-1-imidazolyl 10 CH₃ phenyl 2-methylsulfonyl-1-imidazolyl 11 CH₃ 2-pyridyl 2-(aminosulfonyl)phenyl 12 CH₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl 13 CH₃ 2-pyridyl 1-pyrrolidinocarbonyl 14 CH₃ 2-pyridyl 2-(methylsulfonyl)phenyl 15 CH₃ 2-pyridyl 4-morpholino 16 CH₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 17 CH₃ 2-pyridyl 4-morpholinocarbonyl 18 CH₃ 2-pyridyl 2-methyl-1-imidazolyl 19 CH₃ 2-pyridyl 5-methyl-1-imidazolyl 20 CH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 21 CH₃ 3-pyridyl 2-(aminosulfonyl)phenyl 22 CH₃ 3-pyridyl 2-(methylaminosulfonyl)phenyl 23 CH₃ 3-pyridyl 1-pyrrolidinocarbonyl 24 CH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 25 CH₃ 3-pyridyl 4-morpholino 26 CH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 27 CH₃ 3-pyridyl 4-morpholinocarbonyl 28 CH₃ 3-pyridyl 2-methyl-1-imidazolyl 29 CH₃ 3-pyridyl 5-methyl-1-imidazolyl 30 CH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 31 CH₃ 2-pyrimidyl 2-(aminosulfonyl)phenyl 32 CH₃ 2-pyrimidyl 2-(methylamininosulfonyl)phenyl 33 CH₃ 2-pyrimidyl 1-pyrrolidinocarbonyl 34 CH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 35 CH₃ 2-pyrimidyl 4-morpholino 36 CH₃ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 37 CH₃ 2-pyrimidyl 4-morpholinocarbonyl 38 CH₃ 2-pyrimidyl 2-methyl-1-imidazolyl 39 CH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 40 CH₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 41 CH₃ 5-pyrimidyl 2-(aminosulfonyl)phenyl 42 CH₃ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 43 CH₃ 5-pyrimidyl 1-pyrrolidinocarbonyl 44 CH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl 45 CH₃ 5-pyrimidyl 4-morpholino 46 CH₃ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 47 CH₃ 5-pyrimidyl 4-morpholinocarbonyl 48 CH₃ 5-pyrimidyl 2-methyl-1-imidazolyl 49 CH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 50 CH₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 51 CH₃ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 52 CH₃ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 53 CH₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl 54 CH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 55 CH₃ 2-Cl-phenyl 4-morpholino 56 CH₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 57 CH₃ 2-Cl-phenyl 4-morpholinocarbonyl 58 CH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 59 CH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 60 CH₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 61 CH₃ 2-F-phenyl 2-(aminosulfonyl)phenyl 62 CH₃ 2-F-phenyl 2-(methylaminosulfonyl)phenyl 63 CH₃ 2-F-phenyl 1-pyrrolidinocarbonyl 64 CH₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 65 CH₃ 2-F-phenyl 4-morpholino 66 CH₃ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 67 CH₃ 2-F-phenyl 4-morpholinocarbonyl 68 CH₃ 2-F-phenyl 2-methyl-1-imidazolyl 69 CH₃ 2-F-phenyl 5-methyl-1-imidazolyl 70 CH₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 71 CH₃ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 72 CH₃ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 73 CH₃ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 74 CH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 75 CH₃ 2,6-diF-phenyl 4-morpholino 76 CH₃ 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 77 CH₃ 2,6-diF-phenyl 4-morpholinocarbonyl 78 CH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 79 CH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 80 CH₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 81 CH₂CH₃ phenyl 2-(aminosulfonyl)phenyl 82 CH₂CH₃ phenyl 2-(methylaminosulfonyl)phenyl 83 CH₂CH₃ phenyl 1-pyrrolidinocarbonyl 84 CH₂CH₃ phenyl 2-(methylsulfonyl)phenyl 85 CH₂CH₃ phenyl 4-morpholino 86 CH₂CH₃ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 87 CH₂CH₃ phenyl 4-morpholinocarbonyl 88 CH₂CH₃ phenyl 2-methyl-1-imidazolyl 89 CH₂CH₃ phenyl 5-methyl-1-imidazolyl 90 CH₂CH₃ phenyl 2-methylsulfonyl-1-imidazolyl 91 CH₂CH₃ 2-pyridyl 2-(amininosulfonyl)phenyl 92 CH₂CH₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl 93 CH₂CH₃ 2-pyridyl 1-pyrrolidinocarbonyl 94 CH₂CH₃ 2-pyridyl 2-(methylsulfonyl)phenyl 95 CH₂CH₃ 2-pyridyl 4-morpholino 96 CH₂CH₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 97 CH₂CH₃ 2-pyridyl 4-morpholinocarbonyl 98 CH₂CH₃ 2-pyridyl 2-methyl-1-imidazolyl 99 CH₂CH₃ 2-pyridyl 5-methyl-1-imidazolyl 100 CH₂CH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 101 CH₂CH₃ 3-pyridyl 2-(aminosulfonyl)phenyl 102 CH₂CH₃ 3-pyridyl 2-(methylaminosulfonyl)phenyl 103 CH₂CH₃ 3-pyridyl 1-pyrrolidinocarbonyl 104 CH₂CH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 105 CH₂CH₃ 3-pyridyl 4-morpholino 106 CH₂CH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 107 CH₂CH₃ 3-pyridyl 4-morpholinocarbonyl 108 CH₂CH₃ 3-pyridyl 2-methyl-1-imidazolyl 109 CH₂CH₃ 3-pyridyl 5-methyl-1-imidazolyl 110 CH₂CH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 111 CH₂CH₃ 2-pyrimidyl 2-(aminosulfonyl)phenyl 112 CH₂CH₃ 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 113 CH₂CH₃ 2-pyrimidyl 1-pyrrolidinocarbonyl 114 CH₂CH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 115 CH₂CH₃ 2-pyrimidyl 4-morpholino 116 CH₂CH₃ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 117 CH₂CH₃ 2-pyrimidyl 4-morpholinocarbonyl 118 CH₂CH₃ 2-pyrimidyl 2-methyl-1-imidazolyl 119 CH₂CH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 120 CH₂CH₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 121 CH₂CH₃ 5-pyrimidyl 2-(aminosulfonyl)phenyl 122 CH₂CH₃ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 123 CH₂CH₃ 5-pyrimidyl 1-pyrrolidinocarbonyl 124 CH₂CH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl 125 CH₂CH₃ 5-pyrimidyl 4-morpholino 126 CH₂CH₃ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 127 CH₂CH₃ 5-pyrimidyl 4-morpholinocarbonyl 128 CH₂CH₃ 5-pyrimidyl 2-methyl-1-imidazolyl 129 CH₂CH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 130 CH₂CH₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 131 CH₂CH₃ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 132 CH₂CH₃ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 133 CH₂CH₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl 134 CH₂CH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 135 CH₂CH₃ 2-Cl-phenyl 4-morpholino 136 CH₂CH₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 137 CH₂CH₃ 2-Cl-phenyl 4-morpholinocarbonyl 138 CH₂CH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 139 CH₂CH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 140 CH₂CH₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 141 CH₂CH₃ 2-F-phenyl 2-(aminosulfonyl)phenyl 142 CH₂CH₃ 2-F-phenyl 2-(methylamninosulfonyl)phenyl 143 CH₂CH₃ 2-F-phenyl 1-pyrrolidinocarbonyl 144 CH₂CH₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 145 CH₂CH₃ 2-F-phenyl 4-morpholino 146 CH₂CH₃ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 147 CH₂CH₃ 2-F-phenyl 4-morpholinocarbonyl 148 CH₂CH₃ 2-F-phenyl 2-methyl-1-imidazolyl 149 CH₂CH₃ 2-F-phenyl 5-methyl-1-imidazolyl 150 CH₂CH₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 151 CH₂CH₃ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 152 CH₂CH₃ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 153 CH₂CH₃ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 154 CH₂CH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 155 CH₂CH₃ 2,6-diF-phenyl 4-morpholino 156 CH₂CH₃ 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 157 CH₂CH₃ 2,6-diF-phenyl 4-morpholinocarbonyl 158 CH₂CH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 159 CH₂CH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 160 CH₂CH₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 161 CF₃ phenyl 2-(aminosulfonyl)phenyl 162 CF₃ phenyl 2-(methylaminosulfonyl)phenyl 163 CF₃ phenyl 1-pyrrolidinocarbonyl 164 CF₃ phenyl 2-(methylsulfonyl)phenyl 165 CF₃ phenyl 4-morpholino 166 CF₃ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 167 CF₃ phenyl 4-morpholinocarbonyl 168 CF₃ phenyl 2-methyl-1-imidazolyl 169 CF₃ phenyl 5-methyl-1-imidazolyl 170 CF₃ phenyl 2-methylsulfonyl-1-imidazolyl 171 CF₃ 2-pyridyl 2-(aminosulfonyl)phenyl 172 CF₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl 173 CF₃ 2-pyridyl 1-pyrrolidinocarbonyl 174 CF₃ 2-pyridyl 2-(methylsulfonyl)phenyl 175 CF₃ 2-pyridyl 4-morpholino 176 CF₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 177 CF₃ 2-pyridyl 4-morpholinocarbonyl 178 CF₃ 2-pyridyl 2-methyl-1-imidazolyl 179 CF₃ 2-pyridyl 5-methyl-1-imidazolyl 180 CF₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 181 CF₃ 3-pyridyl 2-(aminosulfonyl)phenyl 182 CF₃ 3-pyridyl 2-(methylaminosulfonyl)phenyl 183 CF₃ 3-pyridyl 1-pyrrolidinocarbonyl 184 CF₃ 3-pyridyl 2-(methylsulfonyl)phenyl 185 CF₃ 3-pyridyl 4-morpholino 186 CF₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 187 CF₃ 3-pyridyl 4-morpholinocarbonyl 188 CF₃ 3-pyridyl 2-methyl-1-imidazolyl 189 CF₃ 3-pyridyl 5-methyl-1-imidazolyl 190 CF₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 191 CF₃ 2-pyrimidyl 2-(aminosulfonyl)phenyl 192 CF₃ 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 193 CF₃ 2-pyrimidyl 1-pyrrolidinocarbonyl 194 CF₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 195 CF₃ 2-pyrimidyl 4-morpholino 196 CF₃ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 197 CF₃ 2-pyrimidyl 4-morpholinocarbonyl 198 CF₃ 2-pyrimidyl 2-methyl-1-imidazolyl 199 CF₃ 2-pyrimidyl 5-methyl-1-imidazolyl 200 CF₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 201 CF₃ 5-pyrimidyl 2-(aminosulfonyl)phenyl 202 CF₃ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 203 CF₃ 5-pyrimidyl 1-pyrrolidinocarbonyl 204 CF₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl 205 CF₃ 5-pyrimidyl 4-morpholino 206 CF₃ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 207 CF₃ 5-pyrimidyl 4-morpholinocarbonyl 208 CF₃ 5-pyrimidyl 2-methyl-1-imidazolyl 209 CF₃ 5-pyrimidyl 5-methyl-1-imidazolyl 210 CF₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 211 CF₃ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 212 CF₃ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 213 CF₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl 214 CF₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 215 CF₃ 2-Cl-phenyl 4-morpholino 216 CF₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 217 CF₃ 2-Cl-phenyl 4-morpholinocarbonyl 218 CF₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 219 CF₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 220 CF₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 221 CF₃ 2-F-phenyl 2-(aminosulfonyl)phenyl 222 CF₃ 2-F-phenyl 2-(methylaminosulfonyl)phenyl 223 CF₃ 2-F-phenyl 1-pyrrolidinocarbonyl 224 CF₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 225 CF₃ 2-F-phenyl 4-morpholino 226 CF₃ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 227 CF₃ 2-F-phenyl 4-morpholinocarbonyl 228 CF₃ 2-F-phenyl 2-methyl-1-imidazolyl 229 CF₃ 2-F-phenyl 5-methyl-1-imidazolyl 230 CF₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 231 CF₃ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 232 CF₃ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 233 CF₃ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 234 CF₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 235 CF₃ 2,6-diF-phenyl 4-morpholino 236 CF₃ 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 237 CF₃ 2,6-diF-phenyl 4-morpholinocarbonyl 238 CF₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 239 CF₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 240 CF₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 241 SCH₃ phenyl 2-(aminosulfonyl)phenyl 242 SCH₃ phenyl 2-(methylaminosulfonyl)phenyl 243 SCH₃ phenyl 1-pyrrolidinocarbonyl 244 SCH₃ phenyl 2-(methylsulfonyl)phenyl 245 SCH₃ phenyl 4-morpholino 246 SCH₃ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 247 SCH₃ phenyl 4-morpholinocarbonyl 248 SCH₃ phenyl 2-methyl-1-imidazolyl 249 SCH₃ phenyl 5-methyl-1-imidazolyl 250 SCH₃ phenyl 2-methylsulfonyl-1-imidazolyl 251 SCH₃ 2-pyridyl 2-(aminosulfonyl)phenyl 252 SCH₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl 253 SCH₃ 2-pyridyl 1-pyrrolidinocarbonyl 254 SCH₃ 2-pyridyl 2-(methylsulfonyl)phenyl 255 SCH₃ 2-pyridyl 4-morpholino 256 SCH₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 257 SCH₃ 2-pyridyl 4-morpholinocarbonyl 258 SCH₃ 2-pyridyl 2-methyl-1-imidazolyl 259 SCH₃ 2-pyridyl 5-methyl-1-imidazolyl 260 SCH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 261 SCH₃ 3-pyridyl 2-(aminosulfonyl)phenyl 262 SCH₃ 3-pyridyl 2-(methylaminosulfonyl)phenyl 263 SCH₃ 3-pyridyl 1-pyrrolidinocarbonyl 264 SCH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 265 SCH₃ 3-pyridyl 4-morpholino 266 SCH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 267 SCH₃ 3-pyridyl 4-morpholinocarbonyl 268 SCH₃ 3-pyridyl 2-methyl-1-imidazolyl 269 SCH₃ 3-pyridyl 5-methyl-1-imidazolyl 270 SCH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 271 SCH₃ 2-pyrimidyl 2-(aminosulfonyl)phenyl 272 SCH₃ 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 273 SCH₃ 2-pyrimidyl 1-pyrrolidinocarbonyl 274 SCH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 275 SCH₃ 2-pyrimidyl 4-morpholino 276 SCH₃ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 277 SCH₃ 2-pyrimidyl 4-morpholinocarbonyl 278 SCH₃ 2-pyrimidyl 2-methyl-1-imidazolyl 279 SCH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 280 SCH₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 281 SCH₃ 5-pyrimidyl 2-(aminosulfonyl)phenyl 282 SCH₃ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 283 SCH₃ 5-pyrimidyl 1-pyrrolidinocarbonyl 284 SCH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl 285 SCH₃ 5-pyrimidyl 4-morpholino 286 SCH₃ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 287 SCH₃ 5-pyrimidyl 4-morpholinocarbonyl 288 SCH₃ 5-pyrimidyl 2-methyl-1-imidazolyl 289 SCH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 290 SCH₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 291 SCH₃ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 292 SCH₃ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 293 SCH₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl 294 SCH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 295 SCH₃ 2-Cl-phenyl 4-morpholino 296 SCH₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 297 SCH₃ 2-Cl-phenyl 4-morpholinocarbonyl 298 SCH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 299 SCH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 300 SCH₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 301 SCH₃ 2-F-phenyl 2-(aminosulfonyl)phenyl 302 SCH₃ 2-F-phenyl 2-(methylamininosulfonyl)phenyl 303 SCH₃ 2-F-phenyl 1-pyrrolidinocarbonyl 304 SCH₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 305 SCH₃ 2-F-phenyl 4-morpholino 306 SCH₃ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 307 SCH₃ 2-F-phenyl 4-morpholinocarbonyl 308 SCH₃ 2-F-phenyl 2-methyl-1-imidazolyl 309 SCH₃ 2-F-phenyl 5-methyl-1-imidazolyl 310 SCH₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 311 SCH₃ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 312 SCH₃ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 313 SCH₃ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 314 SCH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 315 SCH₃ 2,6-diF-phenyl 4-morpholino 316 SCH₃ 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 317 SCH₃ 2,6-diF-phenyl 4-morpholinocarbonyl 318 SCH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 319 SCH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 320 SCH₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 321 SOCH₃ phenyl 2-(aminosulfonyl)phenyl 322 SOCH₃ phenyl 2-(methylaminosulfonyl)phenyl 323 SOCH₃ phenyl 1-pyrrolidinocarbonyl 324 SOCH₃ phenyl 2-(methylsulfonyl)phenyl 325 SOCH₃ phenyl 4-morpholino 326 SOCH₃ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 327 SOCH₃ phenyl 4-morpholinocarbonyl 328 SOCH₃ phenyl 2-methyl-1-imidazolyl 329 SOCH₃ phenyl 5-methyl-1-imidazolyl 330 SOCH₃ phenyl 2-methylsulfonyl-1-imidazolyl 331 SOCH₃ 2-pyridyl 2-(aminosulfonyl)phenyl 332 SOCH₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl 333 SOCH₃ 2-pyridyl 1-pyrrolidinocarbonyl 334 SOCH₃ 2-pyridyl 2-(methylsulfonyl)phenyl 335 SOCH₃ 2-pyridyl 4-morpholino 336 SOCH₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 337 SOCH₃ 2-pyridyl 4-morpholinocarbonyl 338 SOCH₃ 2-pyridyl 2-methyl-1-imidazolyl 339 SOCH₃ 2-pyridyl 5-methyl-1-imidazolyl 340 SOCH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 341 SOCH₃ 3-pyridyl 2-(aminosulfonyl)phenyl 342 SOCH₃ 3-pyridyl 2-(methylaminosulfonyl)phenyl 343 SOCH₃ 3-pyridyl 1-pyrrolidinocarbonyl 344 SOCH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 345 SOCH₃ 3-pyridyl 4-morpholino 346 SOCH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 347 SOCH₃ 3-pyridyl 4-morpholinocarbonyl 348 SOCH₃ 3-pyridyl 2-methyl-1-imidazolyl 349 SOCH₃ 3-pyridyl 5-methyl-1-imidazolyl 350 SOCH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 351 SOCH₃ 2-pyrimidyl 2-(aminosulfonyl)phenyl 352 SOCH₃ 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 353 SOCH₃ 2-pyrimidyl 1-pyrrolidinocarbonyl 354 SOCH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 355 SOCH₃ 2-pyrimidyl 4-morpholino 356 SOCH₃ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 357 SOCH₃ 2-pyrimidyl 4-morpholinocarbonyl 358 SOCH₃ 2-pyrimidyl 2-methyl-1-imidazolyl 359 SOCH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 360 SOCH₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 361 SOCH₃ 5-pyrimidyl 2-(aminosulfonyl)phenyl 362 SOCH₃ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 363 SOCH₃ 5-pyrimidyl 1-pyrrolidinocarbonyl 364 SOCH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl 365 SOCH₃ 5-pyrimidyl 4-morpholino 366 SOCH₃ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 367 SOCH₃ 5-pyrimidyl 4-morpholinocarbonyl 368 SOCH₃ 5-pyrimidyl 2-methyl-1-imidazolyl 369 SOCH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 370 SOCH₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 371 SOCH₃ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 372 SOCH₃ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 373 SOCH₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl 374 SOCH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 375 SOCH₃ 2-Cl-phenyl 4-morpholino 376 SOCH₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 377 SOCH₃ 2-Cl-phenyl 4-morpholinocarbonyl 378 SOCH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 379 SOCH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 380 SOCH₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 381 SOCH₃ 2-F-phenyl 2-(aminosulfonyl)phenyl 382 SOCH₃ 2-F-phenyl 2-(methylamninosulfonyl)phenyl 383 SOCH₃ 2-F-phenyl 1-pyrrolidinocarbonyl 384 SOCH₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 385 SOCH₃ 2-F-phenyl 4-morpholino 386 SOCH₃ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 387 SOCH₃ 2-F-phenyl 4-morpholinocarbonyl 388 SOCH₃ 2-F-phenyl 2-methyl-1-imidazolyl 389 SOCH₃ 2-F-phenyl 5-methyl-1-imidazolyl 390 SOCH₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 391 SOCH₃ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 392 SOCH₃ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 393 SOCH₃ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 394 SOCH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 395 SOCH₃ 2,6-diF-phenyl 4-morpholino 396 SOCH₃ 2,6-diF-phenyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 397 SOCH₃ 2,6-diF-phenyl 4-morpholinocarbonyl 398 SOCH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 399 SOCH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 400 SOCH₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 401 SO₂CH₃ phenyl 2-(aminosulfonyl)phenyl 402 SO₂CH₃ phenyl 2-(methylaminosulfonyl)phenyl 403 SO₂CH₃ phenyl 1-pyrrolidinocarbonyl 404 SO₂CH₃ phenyl 2-(methylsulfonyl)phenyl 405 SO₂CH₃ phenyl 4-morpholino 406 SO₂CH₃ phenyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 407 SO₂CH₃ phenyl 4-morpholinocarbonyl 408 SO₂CH₃ phenyl 2-methyl-1-imidazolyl 409 SO₂CH₃ phenyl 5-methyl-1-imidazolyl 410 SO₂CH₃ phenyl 2-methylsulfonyl-1-imidazolyl 411 SO₂CH₃ 2-pyridyl 2-(aminosulfonyl)phenyl 412 SO₂CH₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl 413 SO₂CH₃ 2-pyridyl 1-pyrrolidinocarbonyl 414 SO₂CH₃ 2-pyridyl 2-(methylsulfonyl)phenyl 415 SO₂CH₃ 2-pyridyl 4-morpholino 416 SO₂CH₃ 2-pyridyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 417 SO₂CH₃ 2-pyridyl 4-morpholinocarbonyl 418 SO₂CH₃ 2-pyridyl 2-methyl-1-imidazolyl 419 SO₂CH₃ 2-pyridyl 5-methyl-1-imidazolyl 420 SO₂CH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 421 SO₂CH₃ 3-pyridyl 2-(aminosulfonyl)phenyl 422 SO₂CH₃ 3-pyridyl 2-(methylaminosulfonyl)phenyl 423 SO₂CH₃ 3-pyridyl 1-pyrrolidinocarbonyl 424 SO₂CH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 425 SO₂CH₃ 3-pyridyl 4-morpholino 426 SO₂CH₃ 3-pyridyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 427 SO₂CH₃ 3-pyridyl 4-morpholinocarbonyl 428 SO₂CH₃ 3-pyridyl 2-methyl-1-imidazolyl 429 SO₂CH₃ 3-pyridyl 5-methyl-1-imidazolyl 430 SO₂CH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 431 SO₂CH₃ 2-pyrimidyl 2-(aminosulfonyl)phenyl 432 SO₂CH₃ 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 433 SO₂CH₃ 2-pyrimidyl 1-pyrrolidinocarbonyl 434 SO₂CH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 435 SO₂CH₃ 2-pyrimidyl 4-morpholino 436 SO₂CH₃ 2-pyrimidyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 437 SO₂CH₃ 2-pyrimidyl 4-morpholinocarbonyl 438 SO₂CH₃ 2-pyrimidyl 2-methyl-1-imidazolyl 439 SO₂CH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 440 SO₂CH₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 441 SO₂CH₃ 5-pyrimidyl 2-(aminosulfonyl)phenyl 442 SO₂CH₃ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 443 SO₂CH₃ 5-pyrimidyl 1-pyrrolidinocarbonyl 444 SO₂CH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl 445 SO₂CH₃ 5-pyrimidyl 4-morpholino 446 SO₂CH₃ 5-pyrimidyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 447 SO₂CH₃ 5-pyrimidyl 4-morpholinocarbonyl 448 SO₂CH₃ 5-pyrimidyl 2-methyl-1-imidazolyl 449 SO₂CH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 450 SO₂CH₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 451 SO₂CH₃ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 452 SO₂CH₃ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 453 SO₂CH₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl 454 SO₂CH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 455 SO₂CH₃ 2-Cl-phenyl 4-morpholino 456 SO₂CH₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 457 SO₂CH₃ 2-Cl-phenyl 4-morpholinocarbonyl 458 SO₂CH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 459 SO₂CH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 460 SO₂CH₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 461 SO₂CH₃ 2-F-phenyl 2-(aminosulfonyl)phenyl 462 SO₂CH₃ 2-F-phenyl 2-(methylaminosulfonyl)phenyl 463 SO₂CH₃ 2-F-phenyl 1-pyrrolidinocarbonyl 464 SO₂CH₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 465 SO₂CH₃ 2-F-phenyl 4-morpholino 466 SO₂CH₃ 2-F-phenyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 467 SO₂CH₃ 2-F-phenyl 4-morpholinocarbonyl 468 SO₂CH₃ 2-F-phenyl 2-methyl-1-imidazolyl 469 SO₂CH₃ 2-F-phenyl 5-methyl-1-imidazolyl 470 SO₂CH₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 471 SO₂CH₃ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 472 SO₂CH₃ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 473 SO₂CH₃ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 474 SO₂CH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 475 SO₂CH₃ 2,6-diF-phenyl 4-morpholino 476 SO₂CH₃ 2,6-diF-phenyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 477 SO₂CH₃ 2,6-diF-phenyl 4-morpholinocarbonyl 478 SO₂CH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 479 SO₂CH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 480 SO₂CH₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 481 CH₂NH phenyl 2-(aminosulfonyl)phenyl —SO₂CH₃ 482 CH₂NH phenyl 2-(methylaminosulfonyl)phenyl —SO₂CH₃ 483 CH₂NH phenyl 1-pyrrolidinocarbonyl —SO₂ CH₃ 484 CH₂NH phenyl 2-(methylsulfonyl)phenyl —SO₂CH₃ 485 CH₂NH phenyl 4-morpholino —SO₂CH₃ 486 CH₂NH phenyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl —SO₂CH₃ 487 CH₂NH phenyl 4-morpholinocarbonyl —SO₂CH₃ 488 CH₂NH phenyl 2-methyl-1-imidazolyl —SO₂CH₃ 489 CH₂NH phenyl 5-methyl-1-imidazolyl —SO₂CH₃ 490 CH₂NH phenyl 2-methylsulfonyl-1-imidazolyl —SO₂CH₃ 491 CH₂NH 2-pyridyl 2-(aminosulfonyl)phenyl —SO₂CH₃ 492 CH₂NH 2-pyridyl 2-(methylaminosulfonyl)phenyl —SO₂CH₃ 493 CH₂NH 2-pyridyl 1-pyrrolidinocarbonyl —SO₂CH₃ 494 CH₂NH 2-pyridyl 2-(methylsulfonyl)phenyl —SO₂CH₃ 495 CH₂NH 2-pyridyl 4-morpholino —SO₂CH₃ 496 CH₂NH 2-pyridyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl —SO₂CH₃ 497 CH₂NH 2-pyridyl 4-morpholinocarbonyl —SO₂CH₃ 498 CH₂NH 2-pyridyl 2-methyl-1-imidazolyl —SO₂CH₃ 499 CH₂NH 2-pyridyl 5-methyl-1-imidazolyl 500 CH₂NH 2-pyridyl 2-methylsulfonyl-1-imidazolyl —SO₂CH₃ 501 CH₂NH 3-pyridyl 2-(aminosulfonyl)phenyl —SO₂CH₃ 502 CH₂NH 3-pyridyl 2-(methylaminosulfonyl)phenyl —SO₂CH₃ 503 CH₂NH 3-pyridyl 1-pyrrolidinocarbonyl —SO₂CH₃ 504 CH₂NH 3-pyridyl 2-(methylsulfonyl)phenyl —SO₂CH₃ 505 CH₂NH 3-pyridyl 4-morpholino —SO₂CH₃ 506 CH₂NH 3-pyridyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl —SO₂CH₃ 507 CH₂NH 3-pyridyl 4-morpholinocarbonyl —SO₂CH₃ 508 CH₂NH 3-pyridyl 2-methyl-1-imidazolyl —SO₂CH₃ 509 CH₂NH 3-pyridyl S-methyl-1-imidazolyl —SO₂CH₃ 510 CH₂NH 3-pyridyl 2-methylsulfonyl-1-imidazolyl SO₂CH₃ 511 CH₂NH 2-pyrimidyl 2-(aminosulfonyl)phenyl —SO₂CH₃ 512 CH₂NH 2-pyrimidyl 2-(methylaminosulfonyl)phenyl —SO₂CH₃ 513 CH₂NH 2-pyrimidyl 1-pyrrolidinocarbonyl —SO₂CH₃ 514 CH₂NH 2-pyrimidyl 2-(methylsulfonyl)phenyl —SO₂CH₃ 515 CH₂NH 2-pyrimidyl 4-morpholino —SO₂CH₃ 516 CH₂NH 2-pyrimidyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl —SO₂CH₃ 517 CH₂NH 2-pyrimidyl 4-morpholinocarbonyl —SO₂ CH₃ 518 CH₂NH 2-pyrimidyl 2-methyl-1-imidazolyl —SO₂CH₃ 519 CH₂NH 2-pyrimidyl 5-methyl-1-imidazolyl —SO₂CH₃ 520 CH₂NH 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl —SO₂ CH₃ 521 CH₂NH 5-pyrimidyl 2-(aminosulfonyl)phenyl —SO₂CH₃ 522 CH₂NH 5-pyrimidyl 2-(methylaminosulfonyl)phenyl —SO₂CH₃ 523 CH₂NH 5-pyrimidyl 1-pyrrolidinocarbonyl —SO₂CH₃ 524 CH₂NH 5-pyrimidyl 2-(methylsulfonyl)phenyl —SO₂CH₃ 525 CH₂NH 5-pyrimidyl 4-morpholino —SO₂ CH₃ 526 CH₂NH 5-pyrimidyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl —SO₂CH₃ 527 CH₂NH 5-pyrimidyl 4-morpholinocarbonyl —SO₂CH₃ 528 CH₂NH 5-pyrimidyl 2-methyl-1-imidazolyl —SO₂CH₃ 529 CH₂NH 5-pyrimidyl 5-methyl-1-imidazolyl —SO₂CH₃ 530 CH₂NH 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl —SO₂CH₃ 531 CH₂NH 2-Cl-phenyl 2-(amininosulfonyl)phenyl —SO₂CH₃ 532 CH₂NH 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl —SO₂CH₃ 533 CH₂NH 2-Cl-phenyl 1-pyrrolidinocarbonyl —SO₂ CH₃ 534 CH₂NH 2-Cl-phenyl 2-(methylsulfonyl)phenyl —SO₂CH₃ 535 CH₂NH 2-Cl-phenyl 4-morpholino —SO₂CH₃ 536 CH₂NH 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl —SO₂CH₃ 537 CH₂NH 2-Cl-phenyl 4-morpholinocarbonyl —SO₂CH₃ 538 CH₂NH 2-Cl-phenyl 2-methyl-1-imidazolyl —SO₂CH₃ 539 CH₂NH 2-Cl-phenyl 5-methyl-1-imidazolyl —SO₂CH₃ 540 CH₂NH 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl —SO₂CH₃ 541 CH₂NH 2-F-phenyl 2-(aminosulfonyl)phenyl —SO₂CH₃ 542 CH₂NH 2-F-phenyl 2-(methylaminosulfonyl)phenyl —SO₂CH₃ 543 CH₂NH 2-F-phenyl 1-pyrrolidinocarbonyl —SO₂ CH₃ 544 CH₂NH 2-F-phenyl 2-(methylsulfonyl)phenyl —SO₂CH₃ 545 CH₂NH 2-F-phenyl 4-morpholino —SO₂ CH₃ 546 CH₂NH 2-F-phenyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl —SO₂CH₃ 547 CH₂NH 2-F-phenyl 4-morpholinocarbonyl —SO₂CH₃ 548 CH₂NH 2-F-phenyl 2-methyl-1-imidazolyl —SO₂CH₃ 549 CH₂NH 2-F-phenyl S-methyl-1-imidazolyl —SO₂ CH₃ 550 CH₂NH 2-F-phenyl 2-methylsulfonyl-1-imidazolyl —SO₂CH₃ 551 CH₂NH 2,6-diF-phenyl 2-(aminosulfonyl)phenyl —SO₂CH₃ 552 CH₂NH 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl — SO₂CH₃ 553 CH₂NH 2,6-diF-phenyl 1-pyrrolidinocarbonyl —SO₂CH₃ 554 CH₂NH 2,6-diF-phenyl 2-(methylsulfonyl)phenyl —SO₂CH₃ 555 CH₂NH 2,6-diF-phenyl 4-morpholino —SO₂CH₃ 556 CH₂NH 2,6-diF-phenyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl —SO₂CH₃ 557 CH₂NH 2,6-diF-phenyl 4-morpholinocarbonyl —SO₂CH₃ 558 CH₂NH 2,6-diF-phenyl 2-methyl-1-imidazolyl —SO₂CH₃ 559 CH₂NH 2,6-diF-phenyl 5-methyl-1-imidazolyl —SO₂CH₃ 560 CH₂NH 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl —SO₂CH₃ 561 Cl phenyl 2-(aminosulfonyl)phenyl 562 Cl phenyl 2-(methylaminosulfonyl)phenyl 563 Cl phenyl 1-pyrrolidinocarbonyl 564 Cl phenyl 2-(methylsulfonyl)phenyl 565 Cl phenyl 4-morpholino 566 Cl phenyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 567 Cl phenyl 4-morpholinocarbonyl 568 Cl phenyl 2-methyl-1-imidazolyl 569 Cl phenyl 5-methyl-1-imidazolyl 570 Cl phenyl 2-methylsulfonyl-1-imidazolyl 572 Cl 2-pyridyl 2-(aminosulfonyl)phenyl 572 Cl 2-pyridyl 2-(methylaminosulfonyl)phenyl 573 Cl 2-pyridyl 1-pyrrolidinocarbonyl 574 Cl 2-pyridyl 2-(methylsulfonyl)phenyl 575 Cl 2-pyridyl 4-morpholino 576 Cl 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 577 Cl 2-pyridyl 4-morpholinocarbonyl 578 Cl 2-pyridyl 2-methyl-1-imidazolyl 579 Cl 2-pyridyl 5-methyl-1-imidazolyl 580 Cl 2-pyridyl 2-methylsulfonyl-1-imidazolyl 581 Cl 3-pyridyl 2-(aminosulfonyl)phenyl 582 Cl 3-pyridyl 2-(methylaminosulfonyl)phenyl 583 Cl 3-pyridyl 1-pyrrolidinocarbonyl 584 Cl 3-pyridyl 2-(methylsulfonyl)phenyl 585 Cl 3-pyridyl 4-morpholino 586 Cl 3-pyridyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 587 Cl 3-pyridyl 4-morpholinocarbonyl 588 Cl 3-pyridyl 2-methyl-1-imidazolyl 589 Cl 3-pyridyl 5-methyl-1-imidazolyl 590 Cl 3-pyridyl 2-methylsulfonyl-1-imidazolyl 591 Cl 2-pyrimidyl 2-(aminosulfonyl)phenyl 592 Cl 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 593 Cl 2-pyrimidyl 1-pyrrolidinocarbonyl 594 Cl 2-pyrimidyl 2-(methylsulfonyl)phenyl 595 Cl 2-pyrimidyl 4-morpholino 596 Cl 2-pyrimidyi 2-(1′ -CF₃-tetrazol-2-yl)phenyl 597 Cl 2-pyrimidyl 4-morpholinocarbonyl 598 Cl 2-pyrimidyl 2-methyl-1-imidazolyl 599 Cl 2-pyrimidyl 5-methyl-1-imidazolyl 600 Cl 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 601 Cl 5-pyrimidyl 2-(aminosulfonyl)phenyl 602 Cl 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 603 Cl 5-pyrimidyl 1-pyrrolidinocarbonyl 604 Cl 5-pyrimidyl 2-(methylsulfonyl)phenyl 605 Cl 5-pyrimidyl 4-morpholino 606 Cl 5-pyrimidyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 607 Cl 5-pyrimidyl 4-morpholinocarbonyl 608 Cl 5-pyrimidyl 2-methyl-1-imidazolyl 609 Cl 5-pyrimidyl 5-methyl-1-imidazolyl 610 Cl 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 611 Cl 2-Cl-phenyl 2-(aminosulfonyl)phenyl 612 Cl 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 613 Cl 2-Cl-phenyl 1-pyrrolidinocarbonyl 614 Cl 2-Cl-phenyl 2-(methylsulfonyl)phenyl 615 Cl 2-Cl-phenyl 4-morpholino 616 Cl 2-Cl-phenyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 617 Cl 2-Cl-phenyl 4-morpholinocarbonyl 618 Cl 2-Cl-phenyl 2-methyl-1-imidazolyl 619 Cl 2-Cl-phenyl 5-methyl-1-imidazolyl 620 Cl 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 621 Cl 2-F-phenyl 2-(aminosulfonyl)phenyl 622 Cl 2-F-phenyl 2-(methylaminosulfonyl)phenyl 623 Cl 2-F-phenyl 1-pyrrolidinocarbonyl 624 Cl 2-F-phenyl 2-(methylsulfonyl)phenyl 625 Cl 2-F-phenyl 4-morpholino 626 Cl 2-F-phenyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 627 Cl 2-F-phenyl 4-morpholinocarbonyl 628 Cl 2-F-phenyl 2-methyl-1-imidazolyl 629 Cl 2-F-phenyl 5-methyl-1-imidazolyl 630 Cl 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 631 Cl 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 632 Cl 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 633 Cl 2,6-diF-phenyl 1-pyrrolidinocarbonyl 634 Cl 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 635 Cl 2,6-diF-phenyl 4-morpholino 636 Cl 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 637 Cl 2,6-diF-phenyl 4-morpholinocarbonyl 638 Cl 2,6-diF-phenyl 2-methyl-1-imidazolyl 639 Cl 2,6-diF-phenyl 5-methyl-1-imidazolyl 640 Cl 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 641 F phenyl 2-(aminosulfonyl)phenyl 642 F phenyl 2-(methylaminosulfonyl)phenyl 643 F phenyl 1-pyrrolidinocarbonyl 644 F phenyl 2-(methylsulfonyl)phenyl 645 F phenyl 4-morpholino 646 F phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 647 F phenyl 4-morpholinocarbonyl 648 F phenyl 2-methyl-1-imidazolyl 649 F phenyl 5-methyl-1-imidazolyl 650 F phenyl 2-methylsulfonyl-1-imidazolyl 651 F 2-pyridyl 2-(aminosulfonyl)phenyl 652 F 2-pyridyl 2-(methylaminosulfonyl)phenyl 653 F 2-pyridyl 1-pyrrolidinocarbonyl 654 F 2-pyridyl 2-(methylsulfonyl)phenyl 655 F 2-pyridyl 4-morpholino 656 F 2-pyridyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 657 F 2-pyridyl 4-morpholinocarbonyl 658 F 2-pyridyl 2-methyl-1-imidazolyl 659 F 2-pyridyl 5-methyl-1-imidazolyl 660 F 2-pyridyl 2-methylsulfonyl-1-imidazolyl 661 F 3-pyridyl 2-(aminosulfonyl)phenyl 662 F 3-pyridyl 2-(methylaminosulfonyl)phenyl 663 F 3-pyridyl 1-pyrrolidinocarbonyl 664 F 3-pyridyl 2-(methylsulfonyl)phenyl 665 F 3-pyridyl 4-morpholino 666 F 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 667 F 3-pyridyl 4-morpholinocarbonyl 668 F 3-pyridyl 2-methyl-1-imidazolyl 669 F 3-pyridyl 5-methyl-1-imidazolyl 670 F 3-pyridyl 2-methylsulfonyl-1-imidazolyl 671 F 2-pyrimidyl 2-(aminosulfonyl)phenyl 672 F 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 673 F 2-pyrimidyl 1-pyrrolidinocarbonyl 674 F 2-pyrimidyl 2-(methylsulfonyl)phenyl 675 F 2-pyrimidyl 4-morpholino 676 F 2-pyrimidyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 677 F 2-pyrimidyl 4-morpholinocarbonyl 678 F 2-pyrimidyl 2-methyl-1-imidazolyl 679 F 2-pyrimidyl 5-methyl-1-imidazolyl 680 F 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 681 F 5-pyrimidyl 2-(aminosulfonyl)phenyl 682 F 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 683 F 5-pyrimidyl 1-pyrrolidinocarbonyl 684 F 5-pyrimidyl 2-(methylsulfonyl)phenyl 685 F 5-pyrimidyl 4-morpholino 686 F 5-pyrimidyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 687 F 5-pyrimidyl 4-morpholinocarbonyl 688 F 5-pyrimidyl 2-methyl-1-imidazolyl 689 F 5-pyrimidyl 5-methyl-1-imidazolyl 690 F 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 691 F 2-Cl-phenyl 2-(aminosulfonyl)phenyl 692 F 2-Cl-phenyl 2-(methyla.minosulfonyl)phenyl 693 F 2-Cl-phenyl 1-pyrrolidinocarbonyl 694 F 2-Cl-phenyl 2-(methylsulfonyl)phenyl 695 F 2-Cl-phenyl 4-morpholino 696 F 2-Cl-phenyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 697 F 2-Cl-phenyl 4-morpholinocarboflyl 698 F 2-Cl-phenyl 2-methyl-1-imidazoJlyl 699 F 2-Cl-phenyl 5-methyl-1-imidazolyl 700 F 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 701 F 2-F-phenyl 2-(aminosulfonyl)phenyl 702 F 2-F-phenyl 2-(methylaminosulfonyl)phenyl 703 F 2-F-phenyl 1-pyrrolidinocarbonyl 704 F 2-F-phenyl 2-(methylsulfonyl)phenyl 705 F 2-F-phenyl 4-morpholino 706 F 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 707 F 2-F-phenyl 4-morpholinocarbonyl 708 F 2-F-phenyl 2-methyl-1-imidazolyl 709 F 2-F-phenyl 5-methyl-1-imidazolyl 710 F 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 711 F 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 712 F 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 713 F 2,6-diF-phenyl 1-pyrrolidinocarbonyl 714 F 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 715 F 2,6-diF-phenyl 4-morpholino 716 F 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 717 F 2,6-diF-phenyl 4-morpholinocarbonyl 718 F 2,6-diF-phenyl 2-methyl-1-imidazolyl 719 F 2,6-diF-phenyl 5-methyl-1-imidazolyl 720 F 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 721 CO₂CH₃ phenyl 2-(aminosulfonyl)phenyl 722 CO₂CH₃ phenyl 2-(methylaminosulfoflyl)phenyl 723 CO₂CH₃ phenyl 1-pyrrolidinocarbonyl 724 CO₂CH₃ phenyl 2-(methylsulfonyl)phenyl 725 CO₂CH₃ phenyl 4-morpholino 726 CO₂CH₃ phenyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 727 CO₂CH₃ phenyl 4-morpholinocarbonyl 728 CO₂CH₃ phenyl 2-methyl-1-imidazolyl 729 CO₂CH₃ phenyl 5-methyl-1-imidazolyl 730 CO₂CH₃ phenyl 2-methylsulfonyl-1-imidazolyl 731 CO₂CH₃ 2-pyridyl 2-(aminosulfonyl)phenyl 732 CO₂CH₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl 733 CO₂CH₃ 2-pyridyl 1-pyrrolidinocarbonyl 734 CO₂CH₃ 2-pyridyl 2-(methylsulfonyl)phenyl 735 CO₂CH₃ 2-pyridyl 4-morpholino 736 CO₂CH₃ 2-pyridyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 737 CO₂CH₃ 2-pyridyl 4-morpholinocarbonyl 738 CO₂CH₃ 2-pyridyl 2-methyl-1-imidazolyl 739 CO₂CH₃ 2-pyridyl 5-methyl-1-imidazolyl 740 CO₂CH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 741 CO₂CH₃ 3-pyridyl 2-(aminosulfonyl)phenyl 742 CO₂CH₃ 3-pyridyl 2-(methylaminosulfonyl)phenyl 743 CO₂CH₃ 3-pyridyl 1-pyrrolidinocarbonyl 744 CO₂CH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 745 CO₂CH₃ 3-pyridyl 4-morpholino 746 CO₂CH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 747 CO₂CH₃ 3-pyridyl 4-morpholinocarbonyl 748 CO₂CH₃ 3-pyridyl 2-methyl-1-imidazolyl 749 CO₂CH₃ 3-pyridyl 5-methyl-1-imidazolyl 750 CO₂CH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 751 CO₂CH₃ 2-pyrimidyl 2-(aminosulfonyl)phenyl 752 CO₂CH₃ 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 753 CO₂CH₃ 2-pyrimidyl 1-pyrrolidinocarbonyl 754 CO₂CH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 755 CO₂CH₃ 2-pyrimidyl 4-morpholino 756 CO₂CH₃ 2-pyrimidyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 757 CO₂CH₃ 2-pyrimidyl 4-morpholinocarbonyl 758 CO₂CH₃ 2-pyrimidyl 2-methyl-1-imidazolyl 759 CO₂CH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 760 CO₂CH₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 761 CO₂CH₃ 5-pyrimidyl 2-(aminosulfonyl)phenyl 762 CO₂CH₃ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 763 CO₂CH₃ 5-pyrimidyl 1-pyrrolidinocarbonyl 764 CO₂CH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl 765 CO₂CH₃ 5-pyrimidyl 4-morpholino 766 CO₂CH₃ 5-pyrimidyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 767 CO₂CH₃ 5-pyrimidyl 4-morpholinocarbonyl 768 CO₂CH₃ 5-pyrimidyl 2-methyl-1-imidazolyl 769 CO₂CH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 770 CO₂CH₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 771 CO₂CH₃ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 772 CO₂CH₃ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 773 CO₂CH₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl 774 CO₂CH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 775 CO₂CH₃ 2-Cl-phenyl 4-morpholino 776 CO₂CH₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 777 CO₂CH₃ 2-Cl-phenyl 4-morpholinocarbonyl 778 CO₂CH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 779 CO₂CH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 780 CO₂CH₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 781 CO₂CH₃ 2-F-phenyl 2-(aminosulfonyl)phenyl 782 CO₂CH₃ 2-F-phenyl 2-(methylaminosulfonyl)phenyl 783 CO₂CH₃ 2-F-phenyl 1-pyrrolidinocarbonyl 784 CO₂CH₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 785 CO₂CH₃ 2-F-phenyl 4-morpholino 786 CO₂CH₃ 2-F-phenyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 787 CO₂CH₃ 2-F-phenyl 4-morpholinocarbonyl 788 CO₂CH₃ 2-F-phenyl 2-methyl-1-imidazolyl 789 CO₂CH₃ 2-F-phenyl 5-methyl-1-imidazolyl 790 CO₂CH₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 791 CO₂CH₃ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 792 CO₂CH₃ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 793 CO₂CH₃ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 794 CO₂CH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 795 CO₂CH₃ 2,6-diF-phenyl 4-morpholino 796 CO₂CH₃ 2,6-diF-phenyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 797 CO₂CH₃ 2,6-diF-phenyl 4-morpholinocarbonyl 798 CO₂CH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 799 CO₂CH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 800 CO₂CH₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 801 CH₂OCH₃ phenyl 2-(aminosulfonyl)phenyl 802 CH₂OCH₃ phenyl 2-(methylaminosulfonyl)phenyl 803 CH₂OCH₃ phenyl 1-pyrrolidinocarbonyl 804 CH₂OCH₃ phenyl 2-(methylsulfonyl)phenyl 805 CH₂OCH₃ phenyl 4-morpholino 806 CH₂OCH₃ phenyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 807 CH₂OCH₃ phenyl 4-morpholinocarbonyl 808 CH₂OCH₃ phenyl 2-methyl-1-imidazolyl 809 CH₂OCH₃ phenyl 5-methyl-1-imidazolyl 810 CH₂OCH₃ phenyl 2-methylsulfonyl-1-imidazolyl 811 CH₂OCH₃ 2-pyridyl 2-(aminosulfonyl)phenyl 812 CH₂OCH₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl 813 CH₂OCH₃ 2-pyridyl 1-pyrrolidinocarbonyl 814 CH₂OCH₃ 2-pyridyl 2-(methylsulfonyl)phenyl 815 CH₂OCH₃ 2-pyridyl 4-morpholino 816 CH₂OCH₃ 2-pyridyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 817 CH₂OCH₃ 2-pyridyl 4-morpholinocarbonyl 818 CH₂OCH₃ 2-pyridyl 2-methyl-1-imidazolyl 819 CH₂OCH₃ 2-pyridyl 5-methyl-1-imidazolyl 820 CH₂OCH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 821 CH₂OCH₃ 3-pyridyl 2-(aminosulfonyl)phenyl 822 CH₂OCH₃ 3-pyridyl 2-(methylaminosulfonyl)phenyl 823 CH₂OCH₃ 3-pyridyl 1-pyrrolidinocarbonyl 824 CH₂OCH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 825 CH₂OCH₃ 3-pyridyl 4-morpholino 826 CH₂OCH₃ 3-pyridyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 827 CH₂OCH₃ 3-pyridyl 4-morpholinocarbonyl 828 CH₂OCH₃ 3-pyridyl 2-methyl-1-imidazolyl 829 CH₂OCH₃ 3-pyridyl 5-methyl-1-imidazolyl 830 CH₂OCH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 831 CH₂OCH₃ 2-pyrimidyl 2-(aminosulfonyl)phenyl 832 CH₂OCH₃ 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 833 CH₂OCH₃ 2-pyrimidyl 1-pyrrolidinocarbonyl 834 CH₂OCH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 835 CH₂OCH₃ 2-pyrimidyl 4-morpholino 836 CH₂OCH₃ 2-pyrimidyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 837 CH₂OCH₃ 2-pyrimidyl 4-morpholinocarbonyl 838 CH₂OCH₃ 2-pyrimidyl 2-methyl-1-imidazolyl 839 CH₂OCH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 840 CH₂OCH₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 841 CH₂OCH₃ 5-pyrimidyl 2-(aminosulfonyl)phenyl 842 CH₂OCH₃ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 843 CH₂OCH₃ 5-pyrimidyl 1-pyrrolidinocarbonyl 844 CH₂OCH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl 845 CH₂OCH₃ 5-pyrimidyl 4-morpholino 846 CH₂OCH₃ 5-pyrimidyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 847 CH₂OCH₃ 5-pyrimidyl 4-morpholinocarbonyl 848 CH₂OCH₃ 5-pyrimidyl 2-methyl-1-imidazolyl 849 CH₂OCH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 850 CH₂OCH₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 851 CH₂OCH₃ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 852 CH₂OCH₃ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 853 CH₂OCH₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl 854 CH₂OCH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 855 CH₂OCH₃ 2-Cl-phenyl 4-morpholino 856 CH₂OCH₃ 2-Cl-phenyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 857 CH₂OCH₃ 2-Cl-phenyl 4-morpholinocarbonyl 858 CH₂OCH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 859 CH₂OCH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 860 CH₂OCH₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 861 CH₂OCH₃ 2-F-phenyl 2-(aminosulfonyl)phenyl 862 CH₂OCH₃ 2-F-phenyl 2-(methylaminosulfonyl)phenyl 863 CH₂OCH₃ 2-F-phenyl 1-pyrrolidinocarbonyl 864 CH₂OCH₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 865 CH₂OCH₃ 2-F-phenyl 4-morpholino 866 CH₂OCH₃ 2-F-phenyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 867 CH₂OCH₃ 2-F-phenyl 4-morpholinocarbonyl 868 CH₂OCH₃ 2-F-phenyl 2-methyl-1-imidazolyl 869 CH₂OCH₃ 2-F-phenyl 5-methyl-1-imidazolyl 870 CH₂OCH₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 871 CH₂OCH₃ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 872 CH₂OCH₃ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 873 CH₂OCH₃ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 874 CH₂OCH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 875 CH₂OCH₃ 2,6-diF-phenyl 4-morpholino 876 CH₂OCH₃ 2,6-diF-phenyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 877 CH₂OCH₃ 2,6 -diF-phenyl 4-morpholinocarbonyl 878 CH₂OCH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 879 CH₂OCH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 880 CH₂OCH₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazoyl 881 CONH₂ phenyl 2-(aminosulfonyl)phenyl 882 CONH₂ phenyl 2-(methylaminosulfonyl)phenyl 883 CONH₂ phenyl 1-pyrrolidinocarbonyl 884 CONH₂ phenyl 2-(methylsulfonyl)phenyl 885 CONH₂ phenyl 4-morpholino 886 CONH₂ phenyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 887 CONH₂ phenyl 4-morpholinocarbonyl 888 CONH₂ phenyl 2-methyl-1-imidazolyl 889 CONH₂ phenyl 5-methyl-1-imidazolyl 890 CONH₂ phenyl 2-methylsulfonyl-1-imidazoyl 891 CONH₂ 2-pyridyl 2-(aminosulfonyl)phenyl 892 CONH₂ 2-pyridyl 2-(methylaminosulfonyl)phenyl 893 CONH₂ 2-pyridyl 1-pyrrolidinocarbonyl 894 CONH₂ 2-pyridyl 2-(methylsulfonyl)phenyl 895 CONH₂ 2-pyridyl 4-morpholino 896 CONH₂ 2-pyridyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 897 CONH₂ 2-pyridyl 4-morpholinocarbonyl 898 CONH₂ 2-pyridyl 2-methyl-1-imidazolyl 899 CONH₂ 2-pyridyl 5-methyl-1-imidazolyl 900 CONH₂ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 901 CONH₂ 3-pyridyl 2-(aminosulfonyl)phenyl 902 CONH₂ 3-pyridyl 2-(methylaminosulfonyl)phenyl 903 CONH₂ 3-pyridyl 1-pyrrolidinocarbonyl 904 CONH₂ 3-pyridyl 2-(methylsulfonyl)phenyl 905 CONH₂ 3-pyridyl 4-morpholino 906 CONH₂ 3-pyridyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 907 CONH₂ 3-pyridyl 4-morpholinocarfonyl 908 CONH₂ 3-pyridyl 2-methyl-1-imidazolyl 909 CONH₂ 3-pyridyl 5-methyl-1-imidazolyl 910 CONH₂ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 911 CONH₂ 2-pyrimidyl 2-(aminosulfonyl)phenyl 912 CONH₂ 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 913 CONH₂ 2-pyrimidyl 1-pyrrolidinocarbonyl 914 CONH₂ 2-pyrimidyl 2-(methylsulfonyl)phenyl 915 CONH₂ 2-pyrimidyl 4-morpholino 916 CONH₂ 2-pyrimidyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 917 CONH₂ 2-pyrimidyl 4-morpholinocarbonyl 918 CONH₂ 2-pyrimidyl 2-methyl-1-imidazolyl 919 CONH₂ 2-pyrimidyl 5-methyl-1-imidazolyl 920 CONH₂ 2-pyrimidyl 2-methylsulfonyl-1-imidazoyl 921 CONH₂ 5-pyrimidyl 2-(aminosulfonyl)phenyl 922 CONH₂ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 923 CONH₂ 5-pyrimidyl 1-pyrrolidinocarbonyl 924 CONH₂ 5-pyrimidyl 2-(methylsulfonyl)phenyl 925 CONH₂ 5-pyrimidyl 4-morpholino 926 CONH₂ 5-pyrimidyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 927 CONH₂ 5-pyrimidyl 4-morpholinocarbonyl 928 CONH₂ 5-pyrimidyl 2-methyl-1-imidazolyl 929 CONH₂ 5-pyrimidyl 5-methyl-1-imidazolyl 930 CONH₂ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 931 CONH₂ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 932 CONH₂ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 933 CONH₂ 2-Cl-phenyl 1-pyrrolidinocarbonyl 934 CONH₂ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 935 CONH₂ 2-Cl-phenyl 4-morpholino 936 CONH₂ 2-Cl-phenyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 937 CONH₂ 2-Cl-phenyl 4-morpholinocarbonyl 938 CONH₂ 2-Cl-phenyl 2-methyl-1-imidazolyl 939 CONH₂ 2-Cl-phenyl 5-methyl-1-imidazolyl 940 CONH₂ 2-Cl-phenyl 2-methylsulfonyl-1-imidazoyl 941 CONH₂ 2-F-phenyl 2-(aminosulfonyl)phenyl 942 CONH₂ 2-F-phenyl 2-(methylaminosulfonyl)phenyl 943 CONH₂ 2-F-phenyl 1-pyrrolidinocarbonyl 944 CONH₂ 2-F-phenyl 2-(methylsulfonyl)phenyl 945 CONH₂ 2-F-phenyl 4-morpholino 946 CONH₂ 2-F-phenyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 947 CONH₂ 2-F-phenyl 4-morpholinocarbonyl 948 CONH₂ 2-F-phenyl 2-methyl-1-imidazolyl 949 CONH₂ 2-F-phenyl 5-methyl-1-imidazolyl 950 CONH₂ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 951 CONH₂ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 952 CONH₂ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 953 CONH₂ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 954 CONH₂ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 955 CONH₂ 2,6-diF-phenyl 4-morpholino 956 CONH₂ 2,6-diF-phenyl 2-(1′ -CF₃-tetrazol-2-yl)phenyl 957 CONH₂ 2,6-diF-phenyl 4-morpholinocarbonyl 958 CONH₂ 2,6-diF-phenyl 2-methyl-1-imidazolyl 959 CONH₂ 2,6-diF-phenyl 5-methyl-1-imidazolyl 960 CONH₂ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl

TABLE 3

Ex # A B  1 phenyl 2-(aminosulfonyl)phenyl  2 phenyl 2-(methylaminosulfonyl)phenyl  3 phenyl 1-pyrrolidinocarbonyl  4 phenyl 2-(methylsulfonyl)phenyl  5 phenyl 4-morpholino  6 phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl  7 phenyl 4-morpholinocarbonyl  8 phenyl 2-methyl-1-imidazolyl  9 phenyl 5-methyl-1-imidazolyl 10 phenyl 2-methylsulfonyl-1-imidazolyl 11 2-pyridyl 2-(aminosulfonyl)phenyl 12 2-pyridyl 2-(methylaminosulfonyl)phenyl 13 2-pyridyl 1-pyrrolidinocarbonyl 14 2-pyridyl 2-(methylsulfonyl)phenyl 15 2-pyridyl 4-morpholino 16 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 17 2-pyridyl 4-morpholinocarbonyl 18 2-pyridyl 2-methyl-1-imidazolyl 19 2-pyridyl 5-methyl-1-imidazolyl 20 2-pyridyl 2-methylsulfonyl-1-imidazolyl 21 3-pyridyl 2-(aminosulfonyl)phenyl 22 3-pyridyl 2-(methylaminosulfonyl)phenyl 23 3-pyridyl 1-pyrrolidinocarbonyl 24 3-pyridyl 2-(methylsulfonyl)phenyl 25 3-pyridyl 4-morpholino 26 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 27 3-pyridyl 4-morpholinocarbonyl 28 3-pyridyl 2-methyl-1-imidazolyl 29 3-pyridyl 5-methyl-1-imidazolyl 30 3-pyridyl 2-methylsulfonyl-1-imidazolyl 31 2-pyrimidyl 2-(aminosulfonyl)phenyl 32 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 33 2-pyrimidyl 1-pyrrolidinocarbonyl 34 2-pyrimidyl 2-(methylsulfonyl)phenyl 35 2-pyrimidyl 4-morpholino 36 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 37 2-pyrimidyl 4-morpholinocarbonyl 38 2-pyrimidyl 2-methyl-1-imidazolyl 39 2-pyrimidyl 5-methyl-1-imidazolyl 40 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 41 5-pyrimidyl 2-(aminosulfonyl)phenyl 42 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 43 5-pyrimidyl 1-pyrrolidinocarbonyl 44 5-pyrimidyl 2-(methylsulfonyl)phenyl 45 5-pyrimidyl 4-morpholino 46 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 47 5-pyrimidyl 4-morpholinocarbonyl 48 5-pyrimidyl 2-methyl-1-imidazolyl 49 5-pyrimidyl 5-methyl-1-imidazolyl 50 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 51 2-Cl-phenyl 2-(aminosulfonyl)phenyl 52 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 53 2-Cl-phenyl 1-pyrrolidinocarbonyl 54 2-Cl-phenyl 2-(methylsulfonyl)phenyl 55 2-Cl-phenyl 4-morpholino 56 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 57 2-Cl-phenyl 4-morpholinocarbonyl 58 2-Cl-phenyl 2-methyl-1-imidazolyl 59 2-Cl-phenyl 5-methyl-1-imidazolyl 60 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 61 2-F-phenyl 2-(aminosulfonyl)phenyl 62 2-F-phenyl 2-(methylaminosulfonyl)phenyl 63 2-F-phenyl 1-pyrrolidinocarbonyl 64 2-F-phenyl 2-(methylsulfonyl)phenyl 65 2-F-phenyl 4-morpholino 66 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 67 2-F-phenyl 4-morpholinocarbonyl 68 2-F-phenyl 2-methyl-1-imidazolyl 69 2-F-phenyl 5-methyl-1-imidazolyl 70 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 71 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 72 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 73 2,6-diF-phenyl 1-pyrrolidinocarbonyl 74 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 75 2,6-diF-phenyl 4-morpholino 76 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 77 2,6-diF-phenyl 4-morpholinocarbonyl 78 2,6-diF-phenyl 2-methyl-1-imidazolyl 79 2,6-diF-phenyl 5-methyl-1-imidazolyl 80 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl

TABLE 4

Ex # R^(1a) A B  1 CH₃ phenyl 2-(aminosulfonyl)phenyl  2 CH₃ phenyl 2-(methylaminosulfonyl)phenyl  3 CH₃ phenyl 1-pyrrolidinocarbonyl  4 CH₃ phenyl 2-(methylsulfonyl)phenyl  5 CH₃ phenyl 4-morpholino  6 CH₃ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl  7 CH₃ phenyl 4-morpholinocarbonyl  8 CH₃ phenyl 2-methyl-1-imidazolyl  9 CH₃ phenyl 5-methyl-1-imidazolyl  10 CH₃ phenyl 2-methylsulfonyl-1-imidazolyl  11 CH₃ 2-pyridyl 2-(aminosulfonyl)phenyl  12 CH₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl  13 CH₃ 2-pyridyl 1-pyrrolidinocarbonyl  14 CH₃ 2-pyridyl 2-(methylsulfonyl)phenyl  15 CH₃ 2-pyridyl 4-morpholino  16 CH₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl  17 CH₃ 2-pyridyl 4-morpholinocarbonyl  18 CH₃ 2-pyridyl 2-methyl-1-imidazolyl  19 CH₃ 2-pyridyl 5-methyl-1-imidazolyl  20 CH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl  21 CH₃ 3-pyridyl 2-(aminosulfonyl)phenyl  22 CH₃ 3-pyridyl 2-(methylaminosulfonyl)phenyl  23 CH₃ 3-pyridyl 1-pyrrolidinocarbonyl  24 CH₃ 3-pyridyl 2-(methylsulfonyl)phenyl  25 CH₃ 3-pyridyl 4-morpholino  26 CH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl  27 CH₃ 3-pyridyl 4-morpholinocarbonyl  28 CH₃ 3-pyridyl 2-methyl-1-imidazolyl  29 CH₃ 3-pyridyl 5-methyl-1-imidazolyl  30 CH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl  31 CH₃ 2-pyrimidyl 2-(aminosulfonyl)phenyl  32 CH₃ 2-pyrimidyl 2-(methylaminosulfonyl)phenyl  33 CH₃ 2-pyrimidyl 1-pyrrolidinocarbonyl  34 CH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl  35 CH₃ 2-pyrimidyl 4-morpholino  36 CH₃ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl  37 CH₃ 2-pyrimidyl 4-morpholinocarbonyl  38 CH₃ 2-pyrimidyl 2-methyl-1-imidazolyl  39 CH₃ 2-pyrimidyl 5-methyl-1-imidazolyl  40 CH₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl  41 CH₃ 5-pyrimidyl 2-(aminosulfonyl)phenyl  42 CH₃ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl  43 CH₃ 5-pyrimidyl 1-pyrrolidinocarbonyl  44 CH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl  45 CH₃ 5-pyrimidyl 4-morpholino  46 CH₃ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl  47 CH₃ 5-pyrimidyl 4-morpholinocarbonyl  48 CH₃ 5-pyrimidyl 2-methyl-1-imidazolyl  49 CH₃ 5-pyrimidyl 5-methyl-1-imidazolyl  50 CH₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl  51 CH₃ 2-Cl-phenyl 2-(aminosulfonyl)phenyl  52 CH₃ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl  53 CH₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl  54 CH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl  55 CH₃ 2-Cl-phenyl 4-morpholino  56 CH₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl  57 CH₃ 2-Cl-phenyl 4-morpholinocarbonyl  58 CH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl  59 CH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl  60 CH₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl  61 CH₃ 2-F-phenyl 2-(aminosulfonyl)phenyl  62 CH₃ 2-F-phenyl 2-(methylaminosulfonyl)phenyl  63 CH₃ 2-F-phenyl 1-pyrrolidinocarbonyl  64 CH₃ 2-F-phenyl 2-(methylsulfonyl)phenyl  65 CH₃ 2-F-phenyl 4-morpholino  66 CH₃ 2-F-phenyl 2-(1′-CF₃tetrazol-2-yl)phenyl  67 CH₃ 2-F-phenyl 4-morpholinocarbonyl  68 CH₃ 2-F-phenyl 2-methyl-1-imidazolyl  69 CH₃ 2-F-phenyl 5-methyl-1-imidazolyl  70 CH₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl  71 CH₃ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl  72 CH₃ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl  73 CH₃ 2,6-diF-phenyl 1-pyrrolidinocarbonyl  74 CH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl  75 CH₃ 2,6-diF-phenyl 4-morpholino  76 CH₃ 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl  77 CH₃ 2,6-diF-phenyl 4-morpholinocarbonyl  78 CH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl  79 CH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl  80 CH₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl  81 CH₂CH₃ phenyl 2-(aminosulfonyl)phenyl  82 CH₂CH₃ phenyl 2-(methylaminosulfonyl)phenyl  83 CH₂CH₃ phenyl 1-pyrrolidinocarbonyl  84 CH₂CH₃ phenyl 2-(methylsulfonyl)phenyl  85 CH₂CH₃ phenyl 4-morpholino  86 CH₂CH₃ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl  87 CH₂CH₃ phenyl 4-morpholinocarbonyl  88 CH₂CH₃ phenyl 2-methyl-1-imidazolyl  89 CH₂CH₃ phenyl 5-methyl-1-imidazolyl  90 CH₂CH₃ phenyl 2-methylsulfonyl-1-imidazolyl  91 CH₂CH₃ 2-pyridyl 2-(aminosulfonyl)phenyl  92 CH₂CH₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl  93 CH₂CH₃ 2-pyridyl 1-pyrrolidinocarbonyl  94 CH₂CH₃ 2-pyridyl 2-(methylsulfonyl)phenyl  95 CH₂CH₃ 2-pyridyl 4-morpholino  96 CH₂CH₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl  97 CH₂CH₃ 2-pyridyl 4-morpholinocarbonyl  98 CH₂CH₃ 2-pyridyl 2-methyl-1-imidazolyl  99 CH₂CH₃ 2-pyridyl 5-methyl-1-imidazolyl 100 CH₂HC₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 101 CH₂CH₃ 3-pyridyl 2-(aminosulfonyl)phenyl 102 CH₂CH₃ 3-pyridyl 2-(methylaminosulfonyl)phenyl 103 CH₂CH₃ 3-pyridyl 1-pyrrolidinocarbonyl 104 CH₂CH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 105 CH₂CH₃ 3-pyridyl 4-morpholino 106 CH₂CH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 107 CH₂CH₃ 3-pyridyl 4-morpholinocarbonyl 108 CH₂CH₃ 3-pyridyl 2-methyl-1-imidazolyl 109 CH₂CH₃ 3-pyridyl 5-methyl-1-imidazolyl 110 CH₂CH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 111 CH₂CH₃ 2-pyrimidyl 2-(aminosulfonyl)phenyl 112 CH₂CH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 113 CH₂CH₃ 2-pyrimidyl 1-pyrrolidinocarbonyl 114 CH₂CH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 115 CH₂CH₃ 2-pyrimidyl 4-morpholino 116 CH₂CH₃ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 117 CH₂CH₃ 2-pyrimidyl 4-morpholinocarbonyl 118 CH₂CH₃ 2-pyrimidyl 2-methyl-1-imidazolyl 119 CH₂CH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 120 CH₂CH₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 121 CH₂CH₃ 5-pyrimidyl 2-(aminosulfonyl)phenyl 122 CH₂CH₃ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 123 CH₂CH₃ 5-pyrimidyl 1-pyrrolidinocarbonyl 124 CH₂CH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl 125 CH₂CH₃ 5-pyrimidyl 4-morpholino 126 CH₂CH₃ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 127 CH₂CH₃ 5-pyrimidyl 4-morpholinocarbonyl 128 CH₂CH₃ 5-pyrimidyl 2-methyl-1-imidazolyl 129 CH₂CH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 130 CH₂CH₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 131 CH₂CH₃ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 132 CH₂CH₃ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 133 CH₂CH₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl 134 CH₂CH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 135 CH₂CH₃ 2-Cl-phenyl 4-morpholino 136 CH₂CH₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 137 CH₂CH₃ 2-Cl-phenyl 4-morpholinocarbonyl 138 CH₂CH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 139 CH₂CH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 140 CH₂CH₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 141 CH₂CH₃ 2-F-phenyl 2-(aminosulfonyl)phenyl 142 CH₂CH₃ 2-F-phenyl 2-(methylaminosulfonyl)phenyl 143 CH₂CH₃ 2-F-phenyl 1-pyrrolidinocarbonyl 144 CH₂CH₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 145 CH₂CH₃ 2-F-phenyl 4-morpholino 146 CH₂CH₃ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 147 CH₂CH₃ 2-F-phenyl 4-morpholinocarbonyl 148 CH₂CH₃ 2-F-phenyl 2-methyl-1-imidazolyl 149 CH₂CH₃ 2-F-phenyl 5-methyl-1-imidazolyl 150 CH₂CH₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 151 CH₂CH₃ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 152 CH₂CH₃ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 153 CH₂CH₃ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 154 CH₂CH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 155 CH₂CH₃ 2,6-diF-phenyl 4-morpholino 156 CH₂CH₃ 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 157 CH₂CH₃ 2,6-diF-phenyl 4-morpholinocarbonyl 158 CH₂CH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 159 CH₂CH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 160 CH₂CH₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 161 CF₃ phenyl 2-(aminosulfonyl)phenyl 162 CF₃ phenyl 2-(methylaminosulfonyl)phenyl 163 CF₃ phenyl 1-pyrrolidinocarbonyl 164 CF₃ phenyl 2-(methylsulfonyl)phenyl 165 CF₃ phenyl 4-morpholino 166 CF₃ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 167 CF₃ phenyl 4-morpholinocarbonyl 168 CF₃ phenyl 2-methyl-1-imidazolyl 169 CF₃ phenyl 5-methyl-1-imidazolyl 170 CF₃ phenyl 2-methylaminosulfonyl-1-imidazolyl 171 CF₃ 2-pyridyl 2-(aminosulfonyl)phenyl 172 CF₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl 173 CF₃ 2-pyridyl 1-pyrrolidinocarbonyl 174 CF₃ 2-pyridyl 2-(methylsulfonyl)phenyl 175 CF₃ 2-pyridyl 4-morpholino 176 CF₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 177 CF₃ 2-pyridyl 4-morpholinocarbonyl 178 CF₃ 2-pyridyl 2-methyl-1-imidazolyl 179 CF₃ 2-pyridyl 5-methyl-1-imidazolyl 180 CF₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 181 CF₃ 3-pyridyl 2-(aminosulfonyl)phenyl 182 CF₃ 3-pyridyl 2-(methylaminosulfonyl)phenyl 183 CF₃ 3-pyridyl 1-pyrrolidinocarbonyl 184 CF₃ 3-pyridyl 2-(methylsulfonyl)phenyl 185 CF₃ 3-pyridyl 4-morpholino 186 CF₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 187 CF₃ 3-pyridyl 4-morpholinocarbonyl 188 CF₃ 3-pyridyl 2-methyl-1-imidazolyl 189 CF₃ 3-pyridyl 5-methyl-1-imidazolyl 190 CF₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 191 CF₃ 2-pyrimidyl 2-(aminosulfonyl)phenyl 192 CF₃ 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 193 CF₃ 2-pyrimidyl 1-pyrrolidinocarbonyl 194 CF₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 195 CF₃ 2-pyrimidyl 4-morpholino 196 CF₃ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 197 CF₃ 2-pyrimidyl 4-morpholinocarbonyl 198 CF₃ 2-pyrimidyl 2-methyl-1-imidazolyl 199 CF₃ 2-pyrimidyl 5-methyl-1-imidazolyl 200 CF₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 201 CF₃ 5-pyrimidyl 2-(aminosulfonyl)phenyl 202 CF₃ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 203 CF₃ 5-pyrimidyl 1-pyrrolidinocarbonyl 204 CF₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl 205 CF₃ 5-pyrimidyl 4-morpholino 206 CF₃ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 207 CF₃ 5-pyrimidyl 4-morpholinocarbonyl 208 CF₃ 5-pyrimidyl 2-methyl-1-imidazolyl 209 CF₃ 5-pyrimidyl 5-methyl-1-imidazolyl 210 CF₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 211 CF₃ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 212 CF₃ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 213 CF₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl 214 CF₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 215 CF₃ 2-Cl-phenyl 4-morpholino 216 CF₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 217 CF₃ 2-Cl-phenyl 4-morpholinocarbonyl 218 CF₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 219 CF₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 220 CF₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 221 CF₃ 2-F-phenyl 2-(aminosulfonyl)phenyl 222 CF₃ 2-F-phenyl 2-(methylaminosulfonyl)phenyl 223 CF₃ 2-F-phenyl 1-pyrrolidinocarbonyl 224 CF₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 225 CF₃ 2-F-phenyl 4-morpholino 226 CF₃ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 227 CF₃ 2-F-phenyl 4-morpholinocarbonyl 228 CF₃ 2-F-phenyl 2-methyl-1-imidazolyl 229 CF₃ 2-F-phenyl 5-methyl-1-imidazolyl 230 CF₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 231 CF₃ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 232 CF₃ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 233 CF₃ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 234 CF₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 235 CF₃ 2,6-diF-phenyl 4-morpholino 236 CF₃ 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 237 CF₃ 2,6-diF-phenyl 4-morpholinocarbonyl 238 CF₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 239 CF₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 240 CF₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 241 SCH₃ phenyl 2-(aminosulfonyl)phenyl 242 SCH₃ phenyl 2-(methylaminosulfonyl)phenyl 243 SCH₃ phenyl 1-pyrrolidinocarbonyl 244 SCH₃ phenyl 2-(methylsulfonyl)phenyl 245 SCH₃ phenyl 4-morpholino 246 SCH₃ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 247 SCH₃ phenyl 4-morpholinocarbonyl 248 SCH₃ phenyl 2-methyl-1-imidazolyl 249 SCH₃ phenyl 5-methyl-1-imidazolyl 250 SCH₃ phenyl 2-methylsulfonyl-1-imidazolyl 251 SCH₃ 2-pyridyl 2-(aminosulfonyl)phenyl 252 SCH₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl 253 SCH₃ 2-pyridyl 1-pyrrolidinocarbonyl 254 SCH₃ 2-pyridyl 2-(methylsulfonyl)phenyl 255 SCH₃ 2-pyridyl 4-morpholino 256 SCH₃ 2-pyridyl 2-(1′-CF₃tetrazol-2-yl)phenyl 257 SCH₃ 2-pyridyl 4-morpholinocarbonyl 258 SCH₃ 2-pyridyl 2-methyl-1-imidazolyl 259 SCH₃ 2-pyridyl 5-methyl-1-imidazolyl 260 SCH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 261 SCH₃ 3-pyridyl 2-(aminosulfonyl)phenyl 262 SCH₃ 3-pyridyl 2-(methylaminosulfonyl)phenyl 263 SCH₃ 3-pyridyl 1-pyrrolidinocarbonyl 264 SCH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 265 SCH₃ 3-pyridyl 4-morpholino 266 SCH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 267 SCH₃ 3-pyridyl 4-morpholinocarbonyl 268 SCH₃ 3-pyridyl 2-methyl-1-imidazolyl 269 SCH₃ 3-pyridyl 5-methyl-1-imidazolyl 270 SCH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 271 SCH₃ 2-pyrimidyl 2-(aminosulfonyl)phenyl 272 SCH₃ 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 273 SCH₃ 2-pyrimidyl 1-pyrrolidinocarbonyl 274 SCH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 275 SCH₃ 2-pyrimidyl 4-morpholino 276 SCH₃ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 277 SCH₃ 2-pyrimidyl 4-morpholinocarbonyl 278 SCH₃ 2-pyrimidyl 2-methyl-1-imidazolyl 279 SCH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 280 SCH₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 281 SCH₃ 5-pyrimidyl 2-(aminsulfonyl)phenyl 282 SCH₃ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 283 SCH₃ 5-pyrimidyl 1-pyrrolidinocarbonyl 284 SCH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl 285 SCH₃ 5-pyrimidyl 4-morpholino 286 SCH₃ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 287 SCH₃ 5-pyrimidyl 4-morpholinocarbonyl 288 SCH₃ 5-pyrimidyl 2-methyl-1-imidazolyl 289 SCH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 290 SCH₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 291 SCH₃ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 292 SCH₃ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 293 SCH₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl 294 SCH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 295 SCH₃ 2-Cl-phenyl 4-morpholino 296 SCH₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 297 SCH₃ 2-Cl-phenyl 4-morpholinocarbonyl 298 SCH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 299 SCH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 300 SCH₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 301 SCH₃ 2-F-phenyl 2-(aminosulfonyl)phenyl 302 SCH₃ 2-F-phenyl 2-(methylaminosulfonyl)phenyl 303 SCH₃ 2-F-phenyl 1-pyrrolidinocarbonyl 304 SCH₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 305 SCH₃ 2-F-phenyl 4-morpholino 306 SCH₃ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 307 SCH₃ 2-F-phenyl 4-morpholinocarbonyl 308 SCH₃ 2-F-phenyl 2-methyl-1-imidazolyl 309 SCH₃ 2-F-phenyl 5-methyl-1-imidazolyl 310 SCH₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 311 SCH₃ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 312 SCH₃ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 313 SCH₃ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 314 SCH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 315 SCH₃ 2,6-diF-phenyl 4-morpholino 316 SCH₃ 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 317 SCH₃ 2,6-diF-phenyl 4-morpholinocarbonyl 318 SCH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 319 SCH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 320 SCH₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 321 SOCH₃ phenyl 2-(aminosulfonyl)phenyl 322 SOCH₃ phenyl 2-(methylaminosulfonyl)phenyl 323 SOCH₃ phenyl 1-pyrrolidinocarbonyl 324 SOCH₃ phenyl 2-(methylsulfonyl)phenyl 325 SOCH₃ phenyl 4-morpholino 326 SOCH₃ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 327 SOCH₃ phenyl 4-morpholinocarbonyl 328 SOCH₃ phenyl 2-methyl-1-imidazolyl 329 SOCH₃ phenyl 5-methyl-1-imidazolyl 330 SOCH₃ phenyl 2-methylsulfonyl-1-imidazolyl 331 SOCH₃ 2-pyridyl 2-(aminosulfonyl)phenyl 332 SOCH₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl 333 SOCH₃ 2-pyridyl 1-pyrrolidinocarbonyl 334 SOCH₃ 2-pyridyl 2-(methylsulfonyl)phenyl 335 SOCH₃ 2-pyridyl 4-morpholino 336 SOCH₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 337 SOCH₃ 2-pyridyl 4-morpholinocarbonyl 338 SOCH₃ 2-pyridyl 2-methyl-1-imidazolyl 339 SOCH₃ 2-pyridyl 5-methyl-1-imidazolyl 340 SOCH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 341 SOCH₃ 3-pyridyl 2-(aminosulfonyl)phenyl 342 SOCH₃ 3-pyridyl 2-(me5thylaminosulfonyl)phenyl 343 SOCH₃ 3-pyridyl 1-pyrrolidinocarbonyl 344 SOCH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 345 SOCH₃ 3-pyridyl 4-morpholino 346 SOCH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 347 SOCH₃ 3-pyridyl 4-morpholinocarbonyl 348 SOCH₃ 3-pyridyl 2-methyl-1-imidazolyl 349 SOCH₃ 3-pyridyl 5-methyl-1-imidazolyl 350 SOCH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 351 SOCH₃ 2-pyrimidyl 2-(aminosulfonyl)phenyl 352 SOCH₃ 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 353 SOCH₃ 2-pyrimidyl 1-pyrrolidinocarbonyl 354 SOCH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 355 SOCH₃ 2-pyrimidyl 4-morpholino 356 SOCH₃ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 357 SOCH₃ 2-pyrimidyl 4-morpholinocarbonyl 358 SOCH₃ 2-pyrimidyl 2-methyl-1-imidazolyl 359 SOCH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 360 SOCH₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 361 SOCH₃ 5-pyrimidyl 2-(aminosulfonyl)phenyl 362 SOCH₃ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 363 SOCH₃ 5-pyrimidyl 1-pyrrolidinocarbonyl 364 SOCH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl 365 SOCH₃ 5-pyrimidyl 4-morpholino 366 SOCH₃ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 367 SOCH₃ 5-pyrimidyl 4-morpholinocarbonyl 368 SOCH₃ 5-pyrimidyl 2-methyl-1-imidazolyl 369 SOCH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 370 SOCH₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 371 SOCH₃ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 372 SOCH₃ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 373 SOCH₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl 374 SOCH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 375 SOCH₃ 2-Cl-phenyl 4-morpholino 376 SOCH₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 377 SOCH₃ 2-Cl-phenyl 4-morpholinocarbonyl 378 SOCH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 379 SOCH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 380 SOCH₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 381 SOCH₃ 2-F-phenyl 2-(aminosulfonyl)phenyl 382 SOCH₃ 2-F-phenyl 2-(methylaminosulfonyl)phenyl 383 SOCH₃ 2-F-phenyl 1-pyrrolidinocarbonyl 384 SOCH₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 385 SOCH₃ 2-F-phenyl 4-morpholino 386 SOCH₃ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 387 SOCH₃ 2-F-phenyl 4-morpholinocarbonyl 388 SOCH₃ 2-F-phenyl 2-methyl-1-imidazolyl 389 SOCH₃ 2-F-phenyl 5-methyl-1-imidazolyl 390 SOCH₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 391 SOCH₃ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 392 SOCH₃ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 393 SOCH₃ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 394 SOCH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 395 SOCH₃ 2,6-diF-phenyl 4-morpholino 396 SOCH₃ 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 397 SOCH₃ 2,6-diF-phenyl 4-morpholinocarbonyl 398 SOCH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 399 SOCH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 400 SOCH₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 401 SO₂CH₃ phenyl 2-(aminosulfonyl)phenyl 402 SO₂CH₃ phenyl 2-(methylsulfonyl)phenyl 403 SO₂CH₃ phenyl 1-pyrrolidinocarbonyl 404 SO₂CH₃ phenyl 2-(methylsulfonyl)phenyl 405 SO₂CH₃ phenyl 4-morpholino 406 SO₂CH₃ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 407 SO₂CH₃ phenyl 4-morpholinocarbonyl 408 SO₂CH₃ phenyl 2-methyl-1-imidazolyl 409 SO₂CH₃ phenyl 5-methyl-1-imidazolyl 410 SO₂CH₃ phenyl 2-methylsulfonyl-1-imdiazolyl 411 SO₂CH₃ 2-pyridyl 2-(aminosulfonyl)phenyl 412 SO₂CH₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl 413 SO₂CH₃ 2-pyridyl 1-pyrrolidinocarbonyl 414 SO₂CH₃ 2-pyridyl 2-(methylsulfonyl)phenyl 415 SO₂CH₃ 2-pyridyl 4-morpholino 416 SO₂CH₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 417 SO₂CH₃ 2-pyridyl 4-morpholinocarbonyl 418 SO₂CH₃ 2-pyridyl 2-methyl-1-imidazolyl 419 SO₂CH₃ 2-pyridyl 5-methyl-1-imidazolyl 420 SO₂CH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 421 SO₂CH₃ 3-pyridyl 2-(aminosulfonyl)phenyl 422 SO₂CH₃ 3-pyridyl 2-(methylaminosulfonyl)phenyl 423 SO₂CH₃ 3-pyridyl 1-pyrrolidinocarbonyl 424 SO₂CH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 425 SO₂CH₃ 3-pyridyl 4-morpholino 426 SO₂CH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 427 SO₂CH₃ 3-pyridyl 4-morpholinocarbonyl 428 SO₂CH₃ 3-pyridyl 2-methyl-1-imidazolyl 429 SO₂CH₃ 3-pyridyl 5-methyl-1-imidazolyl 430 SO₂CH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 431 SO₂CH₃ 2-pyrimidyl 2-(aminosulfonyl)phenyl 432 SO₂CH₃ 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 433 SO₂CH₃ 2-pyrimidyl 1-pyrrolidinocarbonyl 434 SO₂CH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 435 SO₂CH₃ 2-pyrimidyl 4-morpholino 436 SO₂CH₃ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 437 SO₂CH₃ 2-pyrimidyl 4-morpholinocarbonyl 438 SO₂CH₃ 2-pyrimidyl 2-methyl-1-imidazolyl 439 SO₂CH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 440 SO₂CH₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 441 SO₂CH₃ 5-pyrimidyl 2-(aminosulfonyl)phenyl 442 SO₂CH₃ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 443 SO₂CH₃ 5-pyrimidyl 1-pyrrolidinocarbonyl 444 SO₂CH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl 445 SO₂CH₃ 5-pyrimidyl 4-morpholino 446 SO₂CH₃ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 447 SO₂CH₃ 5-pyrimidyl 4-morpholinocarbonyl 448 SO₂CH₃ 5-pyrimidyl 2-methyl-1-imidazolyl 449 SO₂CH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 450 SO₂CH₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 451 SO₂CH₂ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 452 SO₂CH₃ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 453 SO₂CH₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl 454 SO₂CH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 455 SO₂CH₃ 2-Cl-phenyl 4-morpholino 456 SO₂CH₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 457 SO₂CH₃ 2-Cl-phenyl 4-morpholinocarbonyl 458 SO₂CH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 459 SO₂CH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 460 SO₂CH₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 461 SO₂CH₃ 2-F-phenyl 2-(aminosulfonyl)phenyl 462 SO₂CH₃ 2-F-phenyl 2-(methylaminosulfonyl)phenyl 463 SO₂CH₃ 2-F-phenyl 1-pyrrolidinocarbonyl 464 SO₂CH₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 465 SO₂CH₃ 2-F-phenyl 4-morpholino 466 SO₂CH₃ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 467 SO₂CH₃ 2-F-phenyl 4-morpholinocarbonyl 468 SO₂CH₃ 2-F-phenyl 2-methyl-1-imidazolyl 469 SO₂CH₃ 2-F-phenyl 5-methyl-1-imidazolyl 470 SO₂CH₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 471 SO₂CH₃ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 472 SO₂CH₃ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 473 SO₂CH₃ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 474 SO₂CH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 475 SO₂CH₃ 2,6-diF-phenyl 4-morpholino 476 SO₂CH₃ 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 477 SO₂CH₃ 2,6-diF-phenyl 4-morpholinocarbonyl 478 SO₂CH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 479 SO₂CH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 480 SO₂CH₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 481 CH₂NH—SO₂CH₃ phenyl 2-(aminosulfonyl)phenyl 482 CH₂NH—SO₂CH₃ phenyl 2-(methylaminosulfonyl)phenyl 483 CH₂NH—SO₂CH₃ phenyl 1-pyrrolidinocarbonyl 484 CH₂NH—SO₂CH₃ phenyl 2-(methylsulfonyl)phenyl 485 CH₂NH—SO₂CH₃ phenyl 4-morpholino 486 CH₂NH—SO₂CH₃ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 487 CH₂NH—SO₂CH₃ phenyl 4-morpholinocarbonyl 488 CH₂NH—SO₂CH₃ phenyl 2-methyl-1-imidazolyl 489 CH₂NH—SO₂CH₃ phenyl 5-methyl-1-imidazolyl 490 CH₂NH—SO₂CH₃ phenyl 20methylsulfonyl-1-imidazolyl 491 CH₂NH—SO₂CH₃ 2-pyridyl 2-(aminosulfonyl)phenyl 492 CH₂NH—SO₂CH₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl 493 CH₂NH—SO₂CH₃ 2-pyridyl 1-pyrrolidinocarbonyl 494 CH₂NH—SO₂CH₃ 2-pyridyl 2-(methylsulfonyl)phenyl 495 CH₂NH—SO₂CH₃ 2-pyridyl 4-morpholino 496 CH₂NH—SO₂CH₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 497 CH₂NH—SO₂CH₃ 2-pyridyl 4-morpholinocarbonyl 498 CH₂NH—SO₂CH₃ 2-pyridyl 2-methyl-1-imidazolyl 499 CH₂NH 2-pyridyl 5-methyl-1-imidazolyl 500 CH₂NH—SO₂CH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 501 CH₂NH—SO₂CH₃ 3-pyridyl 2-(aminosulfonyl)phenyl 502 CH₂NH—SO₂CH₃ 3-pyridyl 2-(methylaminosulfonyl)phenyl 503 CH₂NH—SO₂CH₃ 3-pyridyl 1-pyrrolidinocarbonyl 504 CH₂NH—SO₂CH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 505 CH₂NH—SO₂CH₃ 3-pyridyl 4-morpholino 506 CH₂NH—SO₂CH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 507 CH₂NH—SO₂CH₃ 3-pyridyl 4-morpholinocarbonyl 508 CH₂NH—SO₂CH₃ 3-pyridyl 2-methyl-1-imidazolyl 509 CH₂NH—SO₂CH₃ 3-pyridyl 5-methyl-1-imidazolyl 510 CH₂NH—SO₂CH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 511 CH₂NH—SO₂CH₃ 2-pyrimidyl 2-(aminsulfonyl)phenyl 512 CH₂NH—SO₂CH₃ 2-pyrimidyl 2-(methylaminosulfinyl)phenyl 513 CH₂NH—SO₂CH₃ 2-pyrimidyl 1-pyrrolidinocarbonyl 514 CH₂NH—SO₂CH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 515 CH₂NH—SO₂CH₃ 2-pyrimidyl 4-morpholino 516 CH₂NH—SO₂CH₃ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 517 CH₂NH—SO₂CH₃ 2-pyrimidyl 4-morpholinocarbonyl 518 CH₂NH—SO₂CH₃ 2-pyrimidyl 2-methyl-1-imidazolyl 519 CH₂NH—SO₂CH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 520 CH₂NH—SO₂CH₂ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 521 CH₂NH—SO₂CH₃ 5-pyrimidyl 2-(aminosulfonyl)phenyl 522 CH₂NH—SO₂CH₃ 5-pyrimidyl 2-(methylaminsulfonyl)phenyl 523 CH₂NH—SO₂CH₃ 5-pyrimidyl 1-pyrrolidinocarbonyl 524 CH₂NH—SO₂CH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl 525 CH₂NH—SO₂CH₃ 5-pyrimidyl 4-morpholino 526 CH₂NH—SO₂CH₃ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 527 CH₂NH—SO₂CH₃ 5-pyrimidyl 4-morpholinocarbonyl 528 CH₂NH—SO₂CH₃ 5-pyrimidyl 2-methyl-1-imidazolyl 529 CH₂NH—SO₂CH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 530 CH₂NH—SO₂CH₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 531 CH₂NH—SO₂CH₃ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 532 CH₂NH—SO₂CH₃ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 533 CH₂NH—SO₂CH₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl 534 CH₂NH—SO₂CH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 535 CH₂NH—SO₂CH₃ 2-Cl-phenyl 4-morpholino 536 CH₂NH—SO₂CH₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 537 CH₂NH—SO₂CH₃ 2-Cl-phenyl 4-morpholinocarbonyl 538 CH₂NH—SO₂CH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 539 CH₂NH—SO₂CH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 540 CH₂NH—SO₂CH₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 541 CH₂NH—SO₂CH₃ 2-F-phenyl 2-(aminsulfonyl)phenyl 542 CH₂NH—SO₂CH₃ 2-F-phenyl 2-(methyylaminosulfonyl)phenyl 543 CH₂NH—SO₂CH₃ 2-F-phenyl 1-pyrrolidinocarbonyl 544 CH₂NH—SO₂CH₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 545 CH₂NH—SO₂CH₃ 2-F-phenyl 4-morpholino 546 CH₂NH—SO₂CH₃ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 547 CH₂NH—SO₂CH₃ 2-F-phenyl 4-morpholinocarbonyl 548 CH₂NH—SO₂CH₃ 2-F-phenyl 2-methyl-1-imidazolyl 549 CH₂NH—SO₂CH₃ 2-F-phenyl 5-methyl-1-imidazolyl 550 CH₂NH—SO₂CH₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 551 CH₂NH—SO₂CH₃ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 552 CH₂NH—SO₂CH₃ 2,6-diF-phenyl 2-(methylaminosulfonul)phenyl 553 CH₂NH—SO₂CH₃ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 554 CH₂NH—SO₂CH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 555 CH₂NH—SO₂CH₃ 2,6-diF-phenyl 4-morpholino 556 CH₂NH—SO₂CH₃ 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 557 CH₂NH—SO₂CH₃ 2,6-diF-phenyl 4-morpholinocarbonyl 558 CH₂NH—SO₂CH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 559 CH₂NH—SO₂CH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 560 CH₂NH—SO₂CH₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 561 Cl phenyl 2-(aminosulfonyl)phenyl 562 Cl phenyl 2-(methylaminsulfonyl)phenyl 563 Cl phenyl 1-pyrrolidinocarbonyl 564 Cl phenyl 2-(methylsulfonyl)phenyl 565 Cl phenyl 4-morpholino 566 Cl phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 567 Cl phenyl 4-morpholinocarbonyl 568 Cl phenyl 2-methyl-1-imidazolyl 569 Cl phenyl 5-methyl-1-imidazolyl 570 Cl phenyl 2-methylsulfonyl-1-imidazolyl 571 Cl 2-pyridyl 2-(aminosulfonyl)phenyl 572 Cl 2-pyridyl 2-(methylaminsulfonyl)phenyl 573 Cl 2-pyridyl 1-pyrrolidinocarbonyl 574 Cl 2-pyridyl 2-(methylsulfonyl)phenyl 575 Cl 2-pyridyl 4-morpholino 576 Cl 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 577 Cl 2-pyridyl 4-morpholinocarbonyl 578 Cl 2-pyridyl 2-methyl-1-imidazolyl 579 Cl 2-pyridyl 5-methyl-1-imidazolyl 580 Cl 2-pyridyl 2-methylsulfonyl-1-imidazolyl 581 Cl 3-pyridyl 2-(aminosulfonyl)phenyl 582 Cl 3-pyridyl 2-(methylaminosulfonyl)phenyl 583 Cl 3-pyridyl 1-pyrrolidinocarbonyl 584 Cl 3-pyridyl 2-(methylsulfonyl)phenyl 585 Cl 3-pyridyl 4-morpholino 586 Cl 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 587 Cl 3-pyridyl 4-morpholinocarbonyl 588 Cl 3-pyridyl 2-methyl-1-imidazolyl 589 Cl 3-pyridyl 5-methyl-1-imidazolyl 590 Cl 3-pyridyl 2-methylaminsulfonyl-1-imidazolyl 591 Cl 2-pyrimidyl 2-(aminosulfonyl)phenyl 592 Cl 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 593 Cl 2-pyrimidyl 1-pyrrolidinocarbonyl 594 Cl 2-pyrimidyl 2-(methylsulfonyl)phenyl 595 Cl 2-pyrimidyl 4-morpholino 596 Cl 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 597 Cl 2-pyrimidyl 4-morpholinocarbonyl 598 Cl 2-pyrimidyl 2-methyl-1-imidazolyl 599 Cl 2-pyrimidyl 5-methyl-1-imidazolyl 600 Cl 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 601 Cl 5-pyrimidyl 2-(aminosulfonyl)phenyl 602 Cl 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 603 Cl 5-pyrimidyl 1-pyrrolidinocarbonyl 604 Cl 5-pyrimidyl 2-(methylsulfonyl)phenyl 605 Cl 5-pyrimidyl 4-morpholino 606 Cl 5-pyrimidyl 2-(1′-CF₃tetrazol-2-yl)phenyl 607 Cl 5-pyrimidyl 4-morpholinocarbonyl 608 Cl 5-pyrimidyl 2-methyl-1-imidazolyl 609 Cl 5-pyrimidyl 5-methyl-1-imidazolyl 610 Cl 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 611 Cl 2-Cl-phenyl 2-(aminosulfonyl)phenyl 612 Cl 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 613 Cl 2-Cl-phenyl 1-pyrrolidinocarbonyl 614 Cl 2-Cl-phenyl 2-(methylsulfonyl)phenyl 615 Cl 2-Cl-phenyl 4-morpholino 616 Cl 2-Cl-phenyl 2-(1′-CF₃tetrazol-2-yl)phenyl 617 Cl 2-Cl-phenyl 4-morpholinocarbonyl 618 Cl 2-Cl-phenyl 2-methyl-1-imidazolyl 619 Cl 2-Cl-phenyl 5-methyl-1-imidazolyl 620 Cl 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 621 Cl 2-F-phenyl 2-(aminosulfonyl)phenyl 622 Cl 2-F-phenyl 2-(methylaminosulfonyl)phenyl 623 Cl 2-F-phenyl 1-pyrrolidinocarbonyl 624 Cl 2-F-phenyl 2-(methylsulfonyl)phenyl 625 Cl 2-F-phenyl 4-morpholino 626 Cl 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 627 Cl 2-F-phenyl 4-morpholinocarbonyl 628 Cl 2-F-phenyl 2-methyl-1-imidazolyl 629 Cl 2-F-phenyl 5-methyl-1-imidazolyl 630 Cl 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 631 Cl 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 632 Cl 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 633 Cl 2,6-diF-phenyl 1-pyrrolidinocarbonyl 634 Cl 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 635 Cl 2,6-diF-phenyl 4-morpholino 636 Cl 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 637 Cl 2,6-diF-phenyl 4-morpholinocarbonyl 638 Cl 2,6-diF-phenyl 2-methyl-1-imidazolyl 639 Cl 2,6-diF-phenyl 5-methyl-1-imidazolyl 640 Cl 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 641 F phenyl 2-(aminsulfonyl)phenyl 642 F phenyl 2-(methylaminosulfonyl)phenyl 643 F phenyl 1-pyrrolidinocarbonyl 644 F phenyl 2-(methylsulfonyl)phenyl 645 F phenyl 4-morpholino 646 F phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 647 F phenyl 4-morpholinocarbonyl 648 F phenyl 2-methyl-1-imidazolyl 649 F phenyl 5-methyl-1-imidazolyl 650 F phenyl 2-methylsulfonyl-1-imidazolyl 651 F 2-pyridyl 2-(aminosulfonyl)phenyl 652 F 2-pyridyl 2-(methylaminosulfonyl)phenyl 653 F 2-pyridyl 1-pyrrolidonocarbonyl 654 F 2-pyridyl 2-(methylsulfonyl)phenyl 655 F 2-pyridyl 4-morpholino 656 F 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 657 F 2-pyridyl 4-morpholinocarbonyl 658 F 2-pyridyl 2-methyl-1-imidazolyl 659 F 2-pyridyl 5-methyl-1-imidazolyl 660 F 2-pyridyl 2-methylsulfonyl-1-imidazolyl 661 F 3-pyridyl 2-(aminosulfonyl)phenyl 662 F 3-pyridyl 2-(methylaminosulfonyl)phenyl 663 F 3-pyridyl 1-pyrrolidinocarbonyl 664 F 3-pyridyl 2-(methylsulfonyl)phenyl 665 F 3-pyridyl 4-morpholino 666 F 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 667 F 3-pyridyl 4-morpholinocarbonyl 668 F 3-pyridyl 2-methyl-1-imidazolyl 669 F 3-pyridyl 5-methyl-1-imidazolyl 670 F 3-pyridyl 2-methylsulfonyl-1-imidazolyl 671 F 2-pyrimidyl 2-(aminsulfonyl)phenyl 672 F 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 673 F 2-pyrimidyl 1-pyrrolidinocarbonyl 674 F 2-pyrimidyl 2-(methylsulfonyl)phenyl 675 F 2-pyrimidyl 4-morpholino 676 F 2-pyrimidyl 2-(1′-CF₃tetrazol-2-yl)phenyl 677 F 2-pyrimidyl 4-morpholinocarbonyl 678 F 2-pyrimidyl 2-methyl-1-imidazolyl 679 F 2-pyrimidyl 5-methyl-1-imidazolyl 680 F 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 681 F 5-pyrimidyl 2-(aminosulfonyl)phenyl 682 F 5-pyrimidyl 2-(methylaminsulfonyl)phenyl 683 F 5-pyrimidyl 1-pyrrolidinocarbonyl 684 F 5-pyrimidyl 2-(methylsulfonyl)phenyl 685 F 5-pyrimidyl 4-morpholino 686 F 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 687 F 5-pyrimidyl 4-morpholinocarbonyl 688 F 5-pyrimidyl 2-methyl-1-imidazolyl 689 F 5-pyrimidyl 5-methyl-1-imidazolyl 690 F 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 691 F 2-Cl-phenyl 2-(aminosulfonyl)phenyl 692 F 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 693 F 2-Cl-phenyl 1-pyrrolidinocarbonyl 694 F 2-Cl-phenyl 2-(methylsulfonyl)phenyl 695 F 2-Cl-phenyl 4-morpholino 696 F 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 697 F 2-Cl-phenyl 4-morpholinocarbonyl 698 F 2-Cl-phenyl 2-methyl-1-imidazolyl 699 F 2-Cl-phenyl 5-methyl-1-imidazolyl 700 F 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 701 F 2-F-phenyl 2-(aminsulfonyl)phenyl 702 F 2-F-phenyl 2-(methylaminosulfonyl)phenyl 703 F 2-F-phenyl 1-pyrrolidinocarbonyl 704 F 2-F-phenyl 2-(methylsulfonyl)phenyl 705 F 2-F-phenyl 4-morpholino 706 F 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 707 F 2-F-phenyl 4-morpholinocarbonyl 708 F 2-F-phenyl 2-methyl-1-imidazolyl 709 F 2-F-phenyl 5-methyl-1-imidazolyl 710 F 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 711 F 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 712 F 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 713 F 2,6-diF-phenyl 1-pyrrolidinocarbonyl 714 F 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 715 F 2,6-diF-phenyl 4-morpholino 716 F 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 717 F 2,6-diF-phenyl 4-morpholinocarbonyl 718 F 2,6-diF-phenyl 2-methyl-1-imidazolyl 719 F 2,6-diF-phenyl 5-methyl-1-imidazolyl 720 F 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 721 CO₂CH₃ phenyl 2-(aminosulfonyl)phenyl 722 CO₂CH₃ phenyl 2-(methylaminosulfonyl)phenyl 723 CO₂CH₃ phenyl 1-pyrrolidinocarbonyl 724 CO₂CH₃ phenyl 2-(methylsulfonyl)phenyl 725 CO₂CH₃ phenyl 4-morpholino 726 CO₂CH₃ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 727 CO₂CH₃ phenyl 4-morpholinocarbonyl 728 CO₂CH₃ phenyl 2-methyl-1-imidazolyl 729 CO₂CH₃ phenyl 5-methyl-1-imidazolyl 730 CO₂CH₃ phenyl 2-methylsulfonyl-1-imidazolyl 731 CO₂CH₃ 2-pyridyl 2-(aminsulfonyl)phenyl 732 CO₂CH₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl 733 CO₂CH₃ 2-pyridyl 1-pyrrolidinocarbonyl 734 CO₂CH₃ 2-pyridyl 2-(methylsulfonyl)phenyl 735 CO₂CH₃ 2-pyridyl 4-morpholino 736 CO₂CH₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 737 CO₂CH₃ 2-pyridyl 4-morpholinocarbonyl 738 CO₂CH₃ 2-pyridyl 2-methyl-1-imidazolyl 739 CO₂CH₃ 2-pyridyl 5-methyl-1-imidazolyl 740 CO₂CH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 741 CO₂CH₃ 3-pyridyl 2-(aminsulfonyl)phenyl 742 CO₂CH₃ 3-pyridyl 2-(methylaminosulfonyl)phenyl 743 CO₂CH₃ 3-pyridyl 1-pyrrolidinocarbonyl 744 CO₂CH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 745 CO₂CH₃ 3-pyridyl 4-morpholino 746 CO₂CH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 747 CO₂CH₃ 3-pyridyl 4-morpholinocarbonyl 748 CO₂CH₃ 3-pyridyl 2-methyl-1-imidazolyl 749 CO₂CH₃ 3-pyridyl 5-methyl-1-imidazolyl 750 CO₂CH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 751 CO₂CH₃ 2-pyrimidyl 2-(aminosulfonyl)phenyl 752 CO₂CH₃ 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 753 CO₂CH₃ 2-pyrimidyl 1-pyrrolidinocarbonyl 754 CO₂CH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 755 CO₂CH₃ 2-pyrimidyl 4-morpholino 756 CO₂CH₃ 2-pyrimidyl 2-(1′-CF₃tetrazol-2-yl)phenyl 757 CO₂CH₃ 2-pyrimidyl 4-morpholinocarbonyl 758 CO₂CH₃ 2-pyrimidyl 2-methyl-1-imidazolyl 759 CO₂CH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 760 CO₂CH₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 761 CO₂CH₃ 5-pyrimidyl 2-(aminosulfonyl)phenyl 762 CO₂CH₃ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 763 CO₂CH₃ 5-pyrimidyl 1-pyrrolidinocarbonyl 764 CO₂CH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl 765 CO₂CH₃ 5-pyrimidyl 4-morpholino 766 CO₂HC₃ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 767 CO₂CH₃ 5-pyrimidyl 4-morpholinocarbonyl 768 CO₂CH₃ 5-pyrimidyl 2-methyl-1-imidazolyl 769 CO₂CH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 770 CO₂CH₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 771 CO₂CH₃ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 772 CO₂CH₃ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 773 CO₂CH₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl 774 CO₂CH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 775 CO₂CH₃ 2-Cl-phenyl 4-morpholino 776 CO₂CH₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 777 CO₂CH₃ 2-Cl-phenyl 4-morpholinocarbonyl 778 CO₂CH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 779 CO₂CH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 780 CO₂CH₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 781 CO₂CH₃ 2-F-phenyl 2-(aminosulfonyl)phenyl 782 CO₂CH₃ 2-F-phenyl 2-(methylaminosulfonyl)phenyl 783 CO₂CH₃ 2-F-phenyl 1-pyrrolidinocarbonyl 784 CO₂CH₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 785 CO₂CH₃ 2-F-phenyl 4-morpholino 786 CO₂CH₃ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 787 CO₂CH₃ 2-F-phenyl 2-morpholinocarbonyl 788 CO₂CH₃ 2-F-phenyl 2-methyl-1-imidazolyl 789 CO₂CH₃ 2-F-phenyl 5-methyl-1-imidazolyl 790 CO₂CH₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 791 CO₂CH₃ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 792 CO₂CH₃ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 793 CO₂CH₃ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 794 CO₂CH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 795 CO₂CH₃ 2,6-diF-phenyl 4-morpholino 796 CO₂CH₃ 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 797 CO₂CH₃ 2,6-diF-phenyl 4-morpholinocarbonyl 798 CO₂CH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 799 CO₂CH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 800 CO₂CH₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 801 CH₂OCH₃ phenyl 2-(aminosulfonyl)phenyl 802 CH₂OCH₃ phenyl 2-(methylaminosulfonyl)phenyl 803 CH₂OCH₃ phenyl 1-pyrrolidinocarbonyl 804 CH₂OCH₃ phenyl 2-(methylsulfonyl)phenyl 805 CH₂OCH₃ phenyl 4-morpholino 806 CH₂OCH₃ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 807 CH₂OCH₃ phenyl 4-morpholinocarbonyl 808 CH₂OCH₃ phenyl 2-methyl-1-imidazolyl 809 CH₂OCH₃ phenyl 5-methyl-1-imidazolyl 810 CH₂OCH₃ phenyl 2-methylsulfonyl-1-imidazolyl 811 CH₂OCH₃ 2-pyridyl 2-(aminosulfonyl)phenyl 812 CH₂OCH₃ 2-pyridyl 2-(methylaminosulfonyl)phenyl 813 CH₂OCH₃ 2-pyridyl 1-pyrrolidinocarbonyl 814 CH₂OCH₃ 2-pyridyl 2-(methylsulfonyl)phenyl 815 CH₂OCH₃ 2-pyridyl 4-morpholino 816 CH₂OCH₃ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 817 CH₂OCH₃ 2-pyridyl 4-morpholinocarbonyl 818 CH₂OCH₃ 2-pyridyl 2-methyl-1-imidazolyl 819 CH₂OCH₃ 2-pyridyl 5-methyl-1-imidazolyl 820 CH₂OCH₃ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 821 CH₂OCH₃ 3-pyridyl 2-(aminosulfonyl)phenyl 822 CH₂OCH₃ 3-pyridyl 2-(methylaminosulfonyl)phenyl 823 CH₂OCH₃ 3-pyridyl 1-pyrrolidinocarbonyl 824 CH₂OCH₃ 3-pyridyl 2-(methylsulfonyl)phenyl 825 CH₂OCH₃ 3-pyridyl 4-morpholino 826 CH₂OCH₃ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 827 CH₂OCH₃ 3-pyridyl 4-morpholinocarbonyl 828 CH₂OCH₃ 3-pyridyl 2-methyl-1-imidazolyl 829 CH₂OCH₃ 3-pyridyl 5-methyl-1-imidazolyl 830 CH₂OCH₃ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 831 CH₂OCH₃ 2-pyrimidyl 2-(aminosulfonyl)phenyl 832 CH₂OCH₃ 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 833 CH₂OCH₃ 2-pyrimidyl 1-pyrrolidinocarbonyl 834 CH₂OCH₃ 2-pyrimidyl 2-(methylsulfonyl)phenyl 835 CH₂OCH₃ 2-pyrimidyl 4-morpholino 836 CH₂OCH₃ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 837 CH₂OCH₃ 2-pyrimidyl 4-morpholinocarbonyl 838 CH₂OCH₃ 2-pyrimidyl 2-methyl-1-imidazolyl 839 CH₂OCH₃ 2-pyrimidyl 5-methyl-1-imidazolyl 840 CH₂OCH₃ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 841 CH₂OCH₃ 5-pyrimidyl 2-(aminsulfonyl)phenyl 842 CH₂OCH₃ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 843 CH₂OCH₃ 5-pyrimidyl 1-pyrrolidinocarbonyl 844 CH₂OCH₃ 5-pyrimidyl 2-(methylsulfonyl)phenyl 845 CH₂OCH₃ 5-pyrimidyl 4-morpholino 846 CH₂OCH₃ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 847 CH₂OCH₃ 5-pyrimidyl 4-morpholinocarbonyl 848 CH₂OCH₃ 5-pyrimidyl 2-methyl-1-imidazolyl 849 CH₂OCH₃ 5-pyrimidyl 5-methyl-1-imidazolyl 850 CH₂OCH₃ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 851 CH₂OCH₃ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 852 CH₂OCH₃ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 853 CH₂OCH₃ 2-Cl-phenyl 1-pyrrolidinocarbonyl 854 CH₂OCH₃ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 855 CH₂OCH₃ 2-Cl-phenyl 4-morpholino 856 CH₂OCH₃ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 857 CH₂OCH₃ 2-Cl-phenyl 4-morpholinocarbonyl 858 CH₂OCH₃ 2-Cl-phenyl 2-methyl-1-imidazolyl 859 CH₂OCH₃ 2-Cl-phenyl 5-methyl-1-imidazolyl 860 CH₂OCH₃ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 861 CH₂OCH₃ 2-F-phenyl 2-(aminosulfonyl)phenyl 862 CH₂OCH₃ 2-F-phenyl 2-(methylaminosulfonyl)phenyl 863 CH₂OCH₃ 2-F-phenyl 1-pyrrolidinocarbonyl 864 CH₂OCH₃ 2-F-phenyl 2-(methylsulfonyl)phenyl 865 CH₂OCH₃ 2-F-phenyl 4-morpholino 866 CH₂OCH₃ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 867 CH₂OCH₃ 2-F-phenyl 4-morpholinocarbonyl 868 CH₂OCH₃ 2-F-phenyl 2-methyl-1-imidazolyl 869 CH₂OCH₃ 2-F-phenyl 5-methyl-1-imidazolyl 870 CH₂OCH₃ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 871 CH₂OCH₃ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 872 CH₂OCH₃ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 873 CH₂OCH₃ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 874 CH₂OCH₃ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 875 CH₂OCH₃ 2,6-diF-phenyl 4-morpholino 876 CH₂OCH₃ 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 877 CH₂OCH₃ 2,6-diF-phenyl 4-morpholinocarbonyl 878 CH₂OCH₃ 2,6-diF-phenyl 2-methyl-1-imidazolyl 879 CH₂OCH₃ 2,6-diF-phenyl 5-methyl-1-imidazolyl 880 CH₂OCH₃ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl 881 CONH₂ phenyl 2-(aminosulfonyl)phenyl 882 CONH₂ phenyl 2-(methylaminosulfonyl)phenyl 883 CONH₂ phenyl 1-pyrrolidinocarbonyl 884 CONH₂ phenyl 2-(methylsulfonyl)phenyl 885 CONH₂ phenyl 4-morpholino 886 CONH₂ phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 887 CONH₂ phenyl 4-morpholinocarbonyl 888 CONH₂ phenyl 2-methyl-1-imidazolyl 889 CONH₂ phenyl 5-methyl-1-imidazolyl 890 CONH₂ phenyl 2-methylsulfonyl-1-imidazolyl 891 CONH₂ 2-pyridyl 2-(aminosulfonyl)phenyl 892 CONH₂ 2-pyridyl 2-(methylaminosulfonyl)phenyl 893 CONH₂ 2-pyridyl 1-pyrrolidinocarbonyl 894 CONH₂ 2-pyridyl 2-(methylsulfonyl)phenyl 895 CONH₂ 2-pyridyl 4-morpholino 896 CONH₂ 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 897 CONH₂ 2-pyridyl 4-morpholinocarbonyl 898 CONH₂ 2-pyridyl 2-methyl-1-imidazolyl 899 CONH₂ 2-pyridyl 5-methyl-1-imidazolyl 900 CONH₂ 2-pyridyl 2-methylsulfonyl-1-imidazolyl 901 CONH₂ 3-pyridyl 2-(aminosulfonyl)phenyl 902 CONH₂ 3-pyridyl 2-(methylaminosulfonyl)phenyl 903 CONH₂ 3-pyridyl 1-pyrrolidinocarbonyl 904 CONH₂ 3-pyridyl 2-(methylsulfonyl)phenyl 905 CONH₂ 3-pyridyl 4-morpholino 906 CONH₂ 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 907 CONH₂ 3-pyridyl 4-morpholinocarbonyl 908 CONH₂ 3-pyridyl 2-methyl-1-imidazolyl 909 CONH₂ 3-pyridyl 5-methyl-1-imidazolyl 910 CONH₂ 3-pyridyl 2-methylsulfonyl-1-imidazolyl 911 CONH₂ 2-pyrimidyl 2-(aminosulfonyl)phenyl 912 CONH₂ 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 913 CONH₂ 2-pyrimidyl 1-pyrrolidinocarbonyl 914 CONH₂ 2-pyrimidyl 2-(methylsulfonyl)phenyl 915 CONH₂ 2-pyrimidyl 4-morpholino 916 CONH₂ 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 917 CONH₂ 2-pyrimidyl 4-morpholinocarbonyl 918 CONH₂ 2-pyrimidyl 2-methyl-1-imidazolyl 919 CONH₂ 2-pyrimidyl 5-methyl-1-imidazolyl 920 CONH₂ 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 921 CONH₂ 5-pyrimidyl 2-(aminosulfonyl)phenyl 922 CONH₂ 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 923 CONH₂ 5-pyrimidyl 1-pyrrolidinocarbonyl 924 CONH₂ 5-pyrimidyl 2-(methylsulfonyl)phenyl 925 CONH₂ 5-pyrimidyl 4-morpholino 926 CONH₂ 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 927 CONH₂ 5-pyrimidyl 4-morpholinocarbonyl 928 CONH₂ 5-pyrimidyl 2-methyl-1-imidazolyl 929 CONH₂ 5-pyrimidyl 5-methyl-1-imidazolyl 930 CONH₂ 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 931 CONH₂ 2-Cl-phenyl 2-(aminosulfonyl)phenyl 932 CONH₂ 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 933 CONH₂ 2-Cl-phenyl 1-pyrrolidinocarbonyl 934 CONH₂ 2-Cl-phenyl 2-(methylsulfonyl)phenyl 935 CONH₂ 2-Cl-phenyl 4-morpholino 936 CONH₂ 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 937 CONH₂ 2-Cl-phenyl 4-morpholinocarbonyl 938 CONH₂ 2-Cl-phenyl 2-methyl-1-imidazolyl 939 CONH₂ 2-Cl-phenyl 5-methyl-1-imidazolyl 940 CONH₂ 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 941 CONH₂ 2-F-phenyl 2-(aminosulfonyl)phenyl 942 CONH₂ 2-F-phenyl 2-(methylaminosulfonyl)phenyl 943 CONH₂ 2-F-phenyl 1-pyrrolidinocarbonyl 944 CONH₂ 2-F-phenyl 2-(methylsulfonyl)phenyl 945 CONH₂ 2-F-phenyl 4-morpholino 946 CONH₂ 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 947 CONH₂ 2-F-phenyl 4-morpholinocarbonyl 948 CONH₂ 2-F-phenyl 2-methyl-1-imidazolyl 949 CONH₂ 2-F-phenyl 5-methyl-1-imidazolyl 950 CONH₂ 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 951 CONH₂ 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 952 CONH₂ 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 953 CONH₂ 2,6-diF-phenyl 1-pyrrolidinocarbonyl 954 CONH₂ 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 955 CONH₂ 2,6-diF-phenyl 4-morpholino 956 CONH₂ 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 957 CONH₂ 2,6-diF-phenyl 4-morpholinocarbonyl 958 CONH₂ 2,6-diF-phenyl 2-methyl-1-imidazolyl 959 CONH₂ 2,6-diF-phenyl 5-methyl-1-imidazolyl 960 CONH₂ 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl

TABLE 5

a b c

d e f

g h i

j k l

m n o

p q r

s t u

v w x

y z aa

bb cc dd

ee ff gg

hh ii jj

kk ll mm

nn oo pp

qq rr ss

tt uu vv

ww xx yy

zz aaa bbb

ccc ddd eee

fff ggg hhh Ex # A B  1 phenyl 2-(aminosulfonyl)phenyl  2 phenyl 2-(methylaminosulfonyl)phenyl  3 phenyl 1-pyrrolidinocarbonyl  4 phenyl 2-(methylsulfonyl)phenyl  5 phenyl 4-morpholino  6 phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl  7 phenyl 4-morpholinocarbonyl  8 phenyl 2-methyl-1-imidazolyl  9 phenyl 5-methyl-1-imidazolyl 10 phenyl 2-methylsulfonyl-1-imidazolyl 11 2-pyridyl 2-(aminosulfonyl)phenyl 12 2-pyridyl 2-(methylaminosulfonyl)phenyl 13 2-pyridyl 1-pyrrolidinocarbonyl 14 2-pyridyl 2-(methylsulfonyl)phenyl 15 2-pyridyl 4-morpholino 16 2-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 17 2-pyridyl 4-morpholinocarbonyl 18 2-pyridyl 2-methyl-1-imidazolyl 19 2-pyridyl 5-methyl-1-imidazolyl 20 2-pyridyl 2-methylsulfonyl-1-imidazolyl 21 3-pyridyl 2-(aminosulfonyl)phenyl 22 3-pyridyl 2-(methylaminosulfonyl)phenyl 23 3-pyridyl 1-pyrrolidinocarbonyl 24 3-pyridyl 2-(methylsulfonyl)phenyl 25 3-pyridyl 4-morpholino 26 3-pyridyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 27 3-pyridyl 4-morpholinocarbonyl 28 3-pyridyl 2-methyl-1-imidazolyl 29 3-pyridyl 5-methyl-1-imidazolyl 30 3-pyridyl 2-methylsulfonyl-1-imidazolyl 31 2-pyrimidyl 2-(aminosulfonyl)phenyl 32 2-pyrimidyl 2-(methylaminosulfonyl)phenyl 33 2-pyrimidyl 1-pyrrolidinocarbonyl 34 2-pyrimidyl 2-(methylsulfonyl)phenyl 35 2-pyrimidyl 4-morpholino 36 2-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 37 2-pyrimidyl 4-morpholinocarbonyl 38 2-pyrimidyl 2-methyl-1-imidazolyl 39 2-pyrimidyl 5-methyl-1-imidazolyl 40 2-pyrimidyl 2-methylsulfonyl-1-imidazolyl 41 5-pyrimidyl 2-(aminosulfonyl)phenyl 42 5-pyrimidyl 2-(methylaminosulfonyl)phenyl 43 5-pyrimidyl 1-pyrrolidinocarbonyl 44 5-pyrimidyl 2-(methylsulfonyl)phenyl 45 5-pyrimidyl 4-morpholino 46 5-pyrimidyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 47 5-pyrimidyl 4-morpholinocarbonyl 48 5-pyrimidyl 2-methyl-1-imidazolyl 49 5-pyrimidyl 5-methyl-1-imidazolyl 50 5-pyrimidyl 2-methylsulfonyl-1-imidazolyl 51 2-Cl-phenyl 2-(aminosulfonyl)phenyl 52 2-Cl-phenyl 2-(methylaminosulfonyl)phenyl 53 2-Cl-phenyl 1-pyrrolidinocarbonyl 54 2-Cl-phenyl 2-(methylsulfonyl)phenyl 55 2-Cl-phenyl 4-morpholino 56 2-Cl-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 57 2-Cl-phenyl 4-morpholinocarbonyl 58 2-Cl-phenyl 2-methyl-1-imidazolyl 59 2-Cl-phenyl 5-methyl-1-imidazolyl 60 2-Cl-phenyl 2-methylsulfonyl-1-imidazolyl 61 2-F-phenyl 2-(aminosulfonyl)phenyl 62 2-F-phenyl 2-(methylaminosulfonyl)phenyl 63 2-F-phenyl 1-pyrrolidinocarbonyl 64 2-F-phenyl 2-(methylsulfonyl)phenyl 65 2-F-phenyl 4-morpholino 66 2-F-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 67 2-F-phenyl 4-morpholinocarbonyl 68 2-F-phenyl 2-methyl-1-imidazolyl 69 2-F-phenyl 5-methyl-1-imidazolyl 70 2-F-phenyl 2-methylsulfonyl-1-imidazolyl 71 2,6-diF-phenyl 2-(aminosulfonyl)phenyl 72 2,6-diF-phenyl 2-(methylaminosulfonyl)phenyl 73 2,6-diF-phenyl 1-pyrrolidinocarbonyl 74 2,6-diF-phenyl 2-(methylsulfonyl)phenyl 75 2,6-diF-phenyl 4-morpholino 76 2,6-diF-phenyl 2-(1′-CF₃-tetrazol-2-yl)phenyl 77 2,6-diF-phenyl 4-morpholinocarbonyl 78 2,6-diF-phenyl 2-methyl-1-imidazolyl 79 2,6-diF-phenyl 5-methyl-1-imidazolyl 80 2,6-diF-phenyl 2-methylsulfonyl-1-imidazolyl

UTILITY

The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. The term “thromboembolic disorders” as used herein includes arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, unstable angina, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, cerebral embolism, kidney embolisms, and pulmonary embolisms. The anticoagulant effect of compounds of the present invention is believed to be due to inhibition of factor Xa or thrombin.

The effectiveness of compounds of the present invention as inhibitors of factor Xa was determined using purified human factor Xa and synthetic substrate. The rate of factor Xa hydrolysis of chromogenic substrate S2222 (Kabi Pharmacia, Franklin, Ohio) was measured both in the absence and presence of compounds of the present invention. Hydrolysis of the substrate resulted in the release of pNA, which was monitored spectrophotometrically by measuring the increase in absorbance at 405 nM. A decrease in the rate of absorbance change at 405 nm in the presence of inhibitor is indicative of enzyme inhibition. The results of this assay are expressed as inhibitory constant, K_(i).

Factor Xa determinations were made in 0.10 M sodium phosphate buffer, pH 7.5, containing 0.20 M NaCl, and 0.5% PEG 8000. The Michaelis constant, Km, for substrate hydrolysis was determined at 25° C. using the method of Lineweaver and Burk. Values of K_(i) were determined by allowing 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, South Bend, Ind.) to react with the substrate (0.20 mM-1 mM) in the presence of inhibitor. Reactions were allowed to go for 30 minutes and the velocities (rate of absorbance change vs time) were measured in the time frame of 25-30 minutes. The following relationship was used to calculate K_(i) values:

(v _(o) −v _(s))/v _(s) =I/(K _(i)(1+S/K _(m)))

where:

v_(o) is the velocity of the control in the absence of inhibitor;

v_(s) is the velocity in the presence of inhibitor;

I is the concentration of inhibitor;

K_(i) is the dissociation constant of the enzyme:inhibitor complex;

S is the concentration of substrate;

K_(m) is the Michaelis constant.

Using the methodology described above, a number of compounds of the present invention were found to exhibit a K_(i) of ≦10 μM, thereby confirming the utility of the compounds of the present invention as effective Xa inhibitors.

The antithrombotic effect of compounds of the present invention can be demonstrated in a rabbit arterio-venous (AV) shunt thrombosis model. In this model, rabbits weighing 2-3 kg anesthetized with a mixture of xylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) are used. A saline-filled AV shunt device is connected between the femoral arterial and the femoral venous cannulae. The AV shunt device consists of a piece of 6-cm tygon tubing which contains a piece of silk thread. Blood will flow from the femoral artery via the AV-shunt into the femoral vein. The exposure of flowing blood to a silk thread will induce the formation of a significant thrombus. After forty minutes, the shunt is disconnected and the silk thread covered with thrombus is weighed. Test agents or vehicle will be given (i.v., i.p., s.c., or orally) prior to the opening of the AV shunt. The percentage inhibition of thrombus formation is determined for each treatment group. The ID50 values (dose which produces 50% inhibition of thrombus formation) are estimated by linear regression.

The compounds of formula (I) may also be useful as inhibitors of serine proteases, notably human thrombin, plasma kallikrein and plasmin. Because of their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, blood coagulation and inflammation, catalyzed by the aforesaid class of enzymes. Specifically, the compounds have utility as drugs for the treatment of diseases arising from elevated thrombin activity such as myocardial infarction, and as reagents used as anticoagulants in the processing of blood to plasma for diagnostic and other commercial purposes.

Some compounds of the present invention were shown to be direct acting inhibitors of the serine protease thrombin by their ability to inhibit the cleavage of small molecule substrates by thrombin in a purified system. In vitro inhibition constants were determined by the method described by Kettner et al. in J. Biol. Chem. 265, 18289-18297 (1990), herein incorporated by reference. In these assays, thrombin-mediated hydrolysis of the chromogenic substrate S2238 (Helena Laboratories, Beaumont, Tex.) was monitored spectrophotometrically. Addition of an inhibitor to the assay mixture results in decreased absorbance and is indicative of thrombin inhibition. Human thrombin (Enzyme Research Laboratories, Inc., South Bend, Ind.) at a concentration of 0.2 nM in 0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5% PEG 6000, was incubated with various substrate concentrations ranging from 0.20 to 0.02 mM. After 25 to 30 minutes of incubation, thrombin activity was assayed by monitoring the rate of increase in absorbance at 405 nm which arises owing to substrate hydrolysis. Inhibition constants were derived from reciprocal plots of the reaction velocity as a function of substrate concentration using the standard method of Lineweaver and Burk. Using the methodology described above, some compounds of this invention were evaluated and found to exhibit a K_(i) of less than 10 μm, thereby confirming the utility of the compounds of the present invention as effective thrombin inhibitors.

The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. These include other anti-coagulant or coagulation inhibitory agents, anti-platelet or platelet inhibitory agents, thrombin inhibitors, or thrombolytic or fibrinolytic agents.

The compounds are administered to a mammal in a therapeutically effective amount. By “therapeutically effective amount” it is meant an amount of a compound of Formula I that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the disease.

By “administered in combination” or “combination therapy” it is meant that the compound of Formula I and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect. Other anticoagulant agents (or coagulation inhibitory agents) that may be used in combination with the compounds of this invention include warfarin and heparin, as well as other factor Xa inhibitors such as those described in the publications identified above under Background of the Invention.

The term anti-platelet agents (or platelet inhibitory agents), as used herein, denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets. Such agents include, but are not limited to, the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA), and piroxicam are preferred. Other suitable anti-platelet agents include ticlopidine, including pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine is also a preferred compound since it is known to be gentle on the gastro-intestinal tract in use. Still other suitable platelet inhibitory agents include IIb/IIIa antagonists, thromboxane-A2-receptor antagonists and thromboxane-A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof.

The term thrombin inhibitors (or anti-thrombin agents), as used herein, denotes inhibitors of the serine protease thrombin. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrin formation are disrupted. A number of thrombin inhibitors are known to one of skill in the art and these inhibitors are contemplated to be used in combination with the present compounds. Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, heparins, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal a-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin. Boropeptide thrombin inhibitors include compounds described in Kettner et al., U.S. Pat. No. 5,187,157 and European Patent Application Publication Number 293 881 A2, the disclosures of which are hereby incorporated herein by reference. Other suitable boroarginine derivatives and boropeptide thrombin inhibitors include those disclosed in PCT Application Publication Number 92/07869 and European Patent Application Publication Number 471,651 A2, the disclosures of which are hereby incorporated herein by reference.

The term thrombolytics (or fibrinolytic) agents (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator, anistreplase, urokinase or streptokinase, including pharmaceutically acceptable salts or prodrugs thereof. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosure of which is hereby incorporated herein by reference herein. The term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.

Administration of the compounds of Formula I of the invention in combination with such additional therapeutic agent, may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each. A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.

The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the inhibition of factor Xa. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving factor Xa. For example, a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimenter that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound. When developing new assays or protocols, compounds according to the present invention could be used to test their effectiveness.

The compounds of the present invention may also be used in diagnostic assays involving factor Xa. For example, the presence of factor Xa in an unknown sample could be determined by addition of chromogenic substrate S2222 to a series of solutions containing test sample and optionally one of the compounds of the present invention. If production of pNA is observed in the solutions containing test sample, but not in the presence of a compound of the present invention, then one would conclude factor Xa was present.

DOSAGE AND FORMULATION

The compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient,and the effect desired. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion. Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

Compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

Representative useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil may be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules should be washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

Injectable

A parenteral composition suitable for administration by injection may be prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution should be made isotonic with sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so that each 5 mL contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mL of vanillin.

Where the compounds of this invention are combined with other anticoagulant agents, for example, a daily dosage may be about 0.1 to 100 milligrams of the compound of Formula I and about 1 to 7.5 milligrams of the second anticoagulant, per kilogram of patient body weight. For a tablet dosage form, the compounds of this invention generally may be present in an amount of about 5 to 10 milligrams per dosage unit, and the second anti-coagulant in an amount of about 1 to 5 milligrams per dosage unit.

Where the compounds of Formula I are administered in combination with an anti-platelet agent, by way of general guidance, typically a daily dosage may be about 0.01 to 25 milligrams of the compound of Formula I and about 50 to 150 milligrams of the anti-platelet agent, preferably about 0.1 to 1 milligrams of the compound of Formula I and about 1 to 3 milligrams of antiplatelet agents, per kilogram of patient body weight.

Where the compounds of Formula I are adminstered in combination with thrombolytic agent, typically a daily dosage may be about 0.1 to 1 milligrams of the compound of Formula I, per kilogram of patient body weight and, in the case of the thrombolytic agents, the usual dosage of the thrombolyic agent when administered alone may be reduced by about 70-80% when administered with a compound of Formula I.

Where two or more of the foregoing second therapeutic agents are administered with the compound of Formula I, generally the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination.

Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of Formula I and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a lowviscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.

Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise that as specifically described herein. 

What is claimed is:
 1. A compound of formula I:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein; ring M contains, in addition to J, 2 N atoms and R^(1b) is not present; J is N or NH; D is selected from CN, C(═NR⁸)NR⁷R⁹, NHC(═NR⁸)NR⁷R⁹, NR⁸CH(═NR⁷), C(O)NR⁷R⁸, and (CR⁸R⁹)_(t)NR⁷R⁸, provided that D is substituted ortho to G on E; E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, and piperidinyl substituted with 1-2 R; R is selected from H, Cl, F, Br, I, (CH₂)_(t)OR³, C₁₋₄ alkyl, OCF₃, CF₃, C(O)NR⁷R⁸, and (CR⁸R⁹)_(t)NR⁷R⁸; G is absent or is selected from NHCH₂, OCH₂, and SCH₂, provided that when s is 0, then G is attached to a carbon atom on ring M; Z is selected from a C₁₋₄ alkylene, (CH₂)_(r)O(CH₂)_(r), (CH₂)_(r)NR³(CH₂)_(r), (CH₂)_(r)C(O)(CH₂)_(r), (CH₂)_(r)C(O)O(CH₂)_(r), (CH₂)_(r)OC(O)(CH₂)_(r), (CH₂)_(r)C(O)NR³(CH₂)_(r), (CH₂)_(r)NR³C(O)(CH₂)_(r), (CH₂)_(r)OC(O)O(CH₂)_(r), (CH₂)_(r)OC(O)NR³(CH₂)_(r), (CH₂)_(r)NR³C(O)O(CH₂)_(r), (CH₂)_(r)NR³C(O)NR³(CH₂)_(r), (CH₂)_(r)S(O)_(p)(CH₂)_(r), (CH₂)_(r)SO₂NR³(CH₂)_(r), (CH₂)_(r)NR³SO₂(CH₂)_(r), and (CH₂)_(r)NR³SO₂NR³(CH₂)_(r), provided that Z does not form a N—N, N—O, N—S, NCH₂N, NCH₂O, or NCH₂S bond with ring M or group A; R^(1a) and R^(1b) are independently absent or selected from —(CH₂)_(r—R) ^(1′), —CH═CH—R^(1′), NCH₂R^(1″), OCH₂R^(1″), SCH₂R^(1″), NH(CH₂)₂(CH₂)_(t)R^(1′), O(CH₂)₂(CH₂)_(t)R^(1′), and S(CH₂)₂(CH₂)_(t)R^(1′); alternatively, R^(1a) and R^(1b), when attached to adjacent carbon atoms, together with the atoms to which they are attached form a 5-8 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R⁴ and which contains from 0-2 heteroatoms selected from the group consisting of N, O, and S; R^(1′) is selected from H, C₁₋₃ alkyl, F, Cl, Br, I, —CN, —CHO, (CF₂)_(r)CF₃, (CH₂)_(r)OR², NR²R^(2a), C(O)R^(2c), OC(O)R², (CF₂)_(r)CO₂R^(2c), S(O)_(p)R^(2b), NR²(CH₂)_(r)OR², C(═NR^(2c))NR²R^(2a), NR²C(O)R^(2b), NR²C(O)NHR^(2b), NR²C(O)₂R^(2a), OC(O)NR^(2a)R^(2b), C(O)NR²R^(2a), C(O)NR²(CH₂)_(r)OR², SO₂NR²R^(2a), NR²SO₂R^(2b), C₃₋₆ carbocyclic residue substituted with 0-2 R⁴, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁴; R^(1″) is selected from H, CH(CH₂OR²)₂, C(O)R^(2c), C(O)NR²R^(2a), S(O)R^(2b), S(O)₂R^(2b), and SO₂NR²R^(2a); R², at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b); R^(2a), at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b); R^(2b), at each occurrence, is selected from CF₃, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b); R^(2c), at each occurrence, is selected from CF₃, OH, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b); alternatively, R² and R^(2a) combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R^(4b) which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S; alternatively, R² and R^(2a), together with the atom to which they are attached, combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R^(4b) and containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S; R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl; R^(3a), at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl; R^(3c), at each occurrence, is selected from C₁₋₄ alkyl, and phenyl; A is selected from: C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁴, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁴; B is selected from: Y, X—Y, NR²R^(2a), C(═NR²)NR²R^(2a), NR²C(═NR²)NR²R^(2a), C₃₋₁₀ carbocyclic residue substituted with 0-2 R^(4a), and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4a); X is selected from C₁₋₄ alkylene, —CR²(CR²R^(2b)) (CH₂)_(t)—, —C(O)—, —C(═NR^(1″))—, —CR²(NR^(1″)R²)—, —CR²(OR²)—, —CR²(SR²)—, —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —S(O)_(p)—, —S(O)_(p)CR²R^(2a)—, —CR²R^(2a)S(O)_(p)—, —S(O)₂NR²—, —NR²S (O)₂—, —NR²S(O)₂CR²R^(2a)—, —CR²R^(2a)S(O)₂NR²—, —NR²S(O)₂NR²—, —C(O)NR²—, —NR²C(O)—, —C(O)NR²CR²R^(2a)—, —NR²C(O)CR²R^(2a)—, —CR²R^(2a)C(O)NR²—, —CR²R^(2a)NR²C(O)—, —NR²C(O)O—, —OC(O)NR²—, —NR²C(O)NR²—, —NR²—, —NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O, —CR²R^(2a)O—, and —OCR²R^(2a)—; Y is selected from: (CH₂)_(r)NR²R^(2a), provided that X—Y do not form a N—N, O— N, or S—N bond, C₃₋₁₀ carbocyclic residue substituted with 0-2 R^(4a), and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4a); R⁴, at each occurrence, is selected from H, ═O, (CH₂)_(r)OR², F, Cl, Br, I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), NR²C(O)R^(2b), C(O)NR²R^(2a), NR²C(O)NR²R^(2a), C(═NR²)NR²R^(2a), C(═NS(O)₂R⁵)NR²R^(2a), NHC(═NR²)NR²R^(2a), C(O)NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, (CF₂)_(r)CF₃, NCH₂R^(1″), OCH₂R^(1″), SCH₂R^(1″), N(CH₂)₂(CH₂)_(t)R^(1′), O(CH₂)₂(CH₂)_(t)R^(1′), and S(CH₂)₂(CH₂)_(t)R^(1′), alternatively, one R⁴ is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S; R^(4a), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR², (CH₂)_(r)—F, (CH₂)_(r)—Br, (CH₂)_(r)—Cl, Cl, Br, F, I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2c), NR²C(O)R^(2b), C(O)NR²R^(2a), C(O)NH(CH₂)₂NR²R^(2a), NR²C(O)NR²R^(2a), C(═NR²)NR²R^(2a), NHC(═NR²)NR²R^(2a), SO₂NR²R^(2a), NR²SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, C(O)NHSO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, and (CF₂)_(r)CF₃; alternatively, one R^(4a) is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R⁵; R^(4b), at each occurrence, is selected from H, ═O, (CH₂)_(r)OR³, F, Cl, Br, I, C₁₋₄ alkyl, —CN, NO₂, (CH₂)_(r)NR³R^(3a), (CH₂)_(r)C(O)R³, (CH₂)_(r)C(O)OR^(3c), NR³C(O)R^(3a), C(O)NR³R^(3a), NR³C(O)NR³R^(3a), C(═NR³)NR³R^(3a), NR³C(═NR³)NR³R^(3a), SO₂NR³R^(3a), NR³SO₂NR³R^(3a), NR³SO₂—C₁₋₄ alkyl, NR³SO₂CF₃, NR³SO₂-phenyl, S(O)_(p)CF₃, S(O)_(p)—C₁₋₄ alkyl, S(O)_(p)-phenyl, and (CF₂)_(r)CF₃; R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl substituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶; R⁶, at each occurrence, is selected from H, OH, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), NR²C(O)NR²R^(2a), C(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂NR²R^(2a), and NR²SO₂C₁₋₄ alkyl; R⁷, at each occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, (CH₂)n-phenyl, C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl; R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl and (CH₂)n-phenyl; alternatively, R⁷ and R⁸ combine to form a 5 or 6 membered saturated, ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S; R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl and (CH₂)n-phenyl; n, at each occurrence, is selected from 0, 1, 2, and 3; p, at each occurrence, is selected from 0, 1, and 2; r, at each occurrence, is selected from 0, 1, 2, and 3; s, at each occurrence, is selected from 0, 1, and 2; and, t, at each occurrence, is selected from 0, 1, 2, and 3; provided that D—E—G—(CH₂)_(s)— and —Z—A—B are not both benzamidines.
 2. A compound according to claim 1, wherein the compound is of formulae Id-If:

wherein, groups D—E— and —Z—A—B are attached to adjacent atoms on the ring; R is selected from H, Cl, F, Br, I, (CH₂)_(t)OR³, C₁₋₄ alkyl, OCF₃, CF₃, C(O)NR⁷R⁸, and (CR⁸R⁹)_(t)NR⁷R⁸; Z is selected from a CH₂O, OCH₂, CH₂NH, NHCH₂, C(O), CH₂C(O), C(O)CH₂, NHC(O), C(O)NH, CH₂S(O)₂, S(O)₂(CH₂), SO₂NH, and NHSO₂, provided that Z does not form a N—N, N—O, NCH₂N, or NCH₂O bond with ring M or group A; A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R⁴; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl; B is selected from: Y, X—Y, NR²R^(2a), C(═NR²)NR²R^(2a), and NR²C (═NR²)NR²R^(2a); X is selected from C₁₋₄ alkylene, —C(O)—, —C(═NR)—, —CR²(NR²R^(2a))—, —C(O)CR²R^(2a)—, —CR²R^(2a)C(O), —C(O)NR²—, —NR²C(O)—, —C(O)NR²CR²R^(2a)—, —NR²C(O)CR²R^(2a)—, —CR²R^(2a)C(O)NR²—, —CR²R^(2a)NR²C(O)—, —NR²C(O)NR²—, —NR²—, —NR²CR²R^(2a)—, —CR²R^(2a)NR²—, O, —CR²R^(2a)O—, and —CR²R^(2a)—; Y is NR²R^(2a), provided that X—Y do not form a N—N or O—N bond; alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R^(4a); cylcopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl; alternatively, Y is selected from the following bicyclic heteroaryl ring systems:

K is selected from O, S, NH, and N.
 3. A compound according to claim 2, wherein the compound is of formulae IIb-IIc:

wherein; Z is selected from a C(O), CH₂C(O), C(O)CH₂, NHC(O), C(O)NH, C(O)N(CH₃), CH₂S(O)₂, S(O)₂(CH₂), SO₂NH, and NHSO₂, provided that Z does not form a N—N or NCH₂N bond with ring M or group A.
 4. A compound according to claim 3, wherein; E is phenyl substituted with R or 2-pyridyl substituted with R; D is selected from NH₂, NHCH₃, CH₂NH₂, CH₂NHCH₃, CH(CH₃)NH₂, and C(CH₃)₂NH₂, provided that D is substituted ortho to ring M on E; and, R is selected from H, OCH₃, Cl, and F.
 5. A compound according to claim 4, wherein; D—E is selected from 2-aminophenyl, 2-methylaminophenyl, 2-aminomethylphenyl, 4-methoxy-2-aminophenyl, 4-methoxy-2-(methylamino)phenyl, 4-methoxy-2-aminomethylphenyl, 4-methoxy-2-(methylaminomethyl)phenyl, 4-methoxy-2-(1-aminoethyl)phenyl, 4-methoxy-2-(2-amino-2-propyl)phenyl, 4-Cl-2-aminophenyl, 4-Cl-2-(methylamino)phenyl, 4-Cl-2-aminomethylphenyl, 4-Cl-2-(methylaminomethyl)phenyl, 4-Cl-2-(1-aminoethyl)phenyl, 4-Cl-2-(2-amino-2-propyl)phenyl, 4-F-2-aminophenyl, 4-F-2-(methylamino)phenyl, 4-F-2-aminomethylphenyl, 4-F-2-(methylaminomethyl)phenyl, 4-F-2-(1-aminoethyl)phenyl, and 4-F-2-(2-amino-2-propyl)phenyl.
 6. A compound according to claim 3, wherein; Z is C(O)CH₂ and CONH, provided that Z does not form a N—N bond with group A; A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R⁴; B is selected from X—Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R^(4a); R⁴, at each occurrence, is selected from OH, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), and (CF₂)_(r)CF₃; R^(4a) is selected from C₁₋₄ alkyl, CF₃, S(O)_(p)R⁵, (CH₂)_(r)NR²R^(2a), SO₂NR²R^(2a), and 1-CF₃-tetrazol-2-yl; R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, and benzyl; X is CH₂ or C(O); and, Y is selected from pyrrolidino and morpholino.
 7. A compound according to claim 6, wherein; A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and, B is selected from the group: 2-CF₃-phenyl, 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 4-morpholino, 2-(1′-CF₃-tetrazol-2-yl)phenyl, 4-morpholinocarbonyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl, 2-methylsulfonyl-1-imidazolyl and, 5-methyl-1,2,3-triazolyl.
 8. A compound according to claim 3, wherein; E is phenyl substituted with R or 2-pyridyl substituted with R; D is selected from NH₂, NHCH₃, CH₂NH₂, CH₂NHCH₃, CH(CH₃)NH₂, and C(CH₃)₂NH₂, provided that D is substituted ortho to ring M on E; R is selected from H, OCH₃, Cl, and F; Z is C(O)CH₂ or CONH, provided that Z does not form a N—N bond with group A; A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R⁴; and, B is selected from X—Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R^(4a); R⁴, at each occurrence, is selected from OH, (CH₂)_(r)OR², halo, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), and (CF₂)_(r)CF₃; R^(4a) is selected from C₁₋₄ alkyl, CF₃, S(O)_(p)R⁵, (CH₂)_(r)NR²R^(2a), SO₂NR²R^(2a), and 1-CF₃-tetrazol-2-yl; R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, and benzyl; X is CH₂ or C(O); and, Y is selected from pyrrolidino and morpholino.
 9. A compound according to claim 8, wherein; D—E is selected from 2-aminophenyl, 2-methylaminophenyl, 2-aminomethylphenyl, 4-methoxy-2-aminophenyl, 4-methoxy-2-(methylamino)phenyl, 4-methoxy-2-aminomethylphenyl, 4-methoxy-2-(methylaminomethyl)phenyl, 4-methoxy-2-(1-aminoethyl)phenyl, 4-methoxy-2-(2-amino-2-propyl)phenyl, 4-Cl-2-aminophenyl, 4-Cl-2-(methylamino)phenyl, 4-Cl-2-aminomethylphenyl, 4-Cl-2-(methylaminomethyl)phenyl, 4-Cl-2-(1-aminoethyl)phenyl, 4-Cl-2-(2-amino-2-propyl)phenyl, 4-F-2-aminophenyl, 4-F-2-(methylamino)phenyl, 4-F-2-aminomethylphenyl, 4-F-2-(methylaminomethyl)phenyl, 4-F-2-(1-aminoethyl)phenyl, and 4-F-2-(2-amino-2-propyl)phenyl; A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and, B is selected from the group: 2-CF₃-phenyl, 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 4-morpholino, 2-(1′-CF₃-tetrazol-2-yl)phenyl, 4-morpholinocarbonyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl, 2-methylsulfonyl-1-imidazolyl and, 5-methyl-1,2,3-triazolyl.
 10. A compound according to claim 9, wherein the compound is of formula IIb.
 11. A compound according to claim 9, wherein the compound is of formula IIb.
 12. A compound according to claim 3, wherein; D is selected from —CN, C(═NR⁸)NR⁷R⁹, C(O)NR⁷R⁸, NR⁷R⁸, and CH₂NR⁷R⁸, provided that D is substituted ortho to ring M on E; E is phenyl substituted with R or pyridyl substituted with R; R is selected from H, Cl, F, OR³, CH₃, CH₂CH₃, OCF₃, CF₃, NR⁷R⁸, and CH₂NR⁷R⁸; Z is selected from C(O), CH₂C(O), C(O)CH₂, NHC(O), and C(O)NH, provided that Z does not form a N—N bond with ring M or group A; R^(1a) and R^(1b) are independently absent or selected from —(CH₂)_(r)—R^(1′), NCH₂R^(1″), OCH₂R^(1″), SCH₂R^(1″), N(CH₂)₂(CH₂)_(t)R^(1′), O(CH₂)₂(CH₂)_(t)R^(1′), and S(CH₂)₂(CH₂)_(t)R^(1′), or combine to form a 5-8 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R⁴ and which contains from 0-2 heteroatoms selected from the group consisting of N, O, and S; R^(1′), at each occurrence, is selected from H, C₁₋₃ alkyl, halo, (CF₂)_(r)CF₃, OR², NR²R^(2a), C(O)R^(2c), (CF₂)_(r)CO₂R^(2c), S(O)_(p)R^(2b), NR²(CH₂)_(r)OR², NR²C(O)R^(2b), NR²C(O)₂R^(2b), C(O)NR²R^(2a), SO₂NR²R^(2a), and NR²SO₂R^(2b); A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R⁴; phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl; B is selected from: Y, X—Y, NR²R^(2a), C(═NR²)NR²R^(2a), and NR²C(═NR²)NR²R^(2a); X is selected from CH₂, —CR²(CR²R^(2b)) (CH₂)_(t)—, —C(O)—, —C(═NR)—, —CH(NR²R^(2a))—, —C(O)NR²—, —NR²C(O)—, —NR²C(O)NR²—, —NR²—, and O; Y is NR²R^(2a), provided that X—Y do not form a N—N or O—N bond; alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R^(4a); phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl; R⁴, at each occurrence, is selected from ═O, OH, Cl, F, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), C(O)NR²R^(2a), C(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, and (CF₂)_(r)CF₃; R^(4a), at each occurrence, is selected from ═O, OH, Cl, F, C₁₋₄ alkyl, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), C(O)NR²R^(2a), C(═NH)NH₂, NHC(═NH)NH₂, SO₂NR²R^(2a), NR²SO₂—C₁₋₄ alkyl, NR²SO₂R⁵, S(O)_(p)R⁵, (CF₂)_(r)CF₃, and 1—CF₃-tetrazol-2-yl; R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl substituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶; R⁶, at each occurrence, is selected from H, ═O, OH, OR², Cl, F, CH₃, CN, NO₂, (CH₂)_(r)NR²R^(2a), (CH₂)_(r)C(O)R^(2b), NR²C(O)R^(2b), C(═NH)NH₂, NHC(═NH)NH₂, and SO₂NR²R^(2a); R⁷, at each occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, benzyl, C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl; R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl and benzyl; alternatively, R⁷ and R⁸ combine to form a morpholino group; and, R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl and benzyl.
 13. A compound according to claim 12, wherein; E is phenyl substituted with R or 2-pyridyl substituted with R; R is selected from H, Cl, F, OCH₃, CH₃, OCF₃, CF₃, NH₂, and CH₂NH₂; z is selected from C(O)CH₂ and C(O)NH, provided that Z does not form a N—N bond with group A; R^(1a) is selected from H, CH₃, CH₂CH₃, Cl, F, CF₃, OCH₃, NR²R^(2a), S(O)_(p)R^(2b), CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2c), CH₂C(O)R^(2c), C(O)NR²R^(2a), and SO₂NR²R^(2a); R^(1b) is selected from H, CH₃, CH₂CH₃, Cl, F, CF₃, OCH₃, NR²R^(2a), S(O)_(p)R^(2b), CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2c), CH₂C(O)R^(2c), C(O)NR²R^(2a), and SO₂NR²R^(2a); A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R⁴; phenyl, pyridyl, pyrimidyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl; B is selected from: Y and X—Y; X is selected from CH₂, —CR²(CR²R^(2b))—, —C(═NR)—, —C(═NR)—, —CH(NR²R^(2a))—, —C(O)NR²—, —NR²C(O)—, —NR²C(O)NR²—, —NR²—, and O; Y is NR²R^(2a), provided that X—Y do not form a N—N or O—N bond; alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R^(4a); phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl; R², at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl; R^(2a), at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl; R^(2b), at each occurrence, is selected from CF₃, OCH₃, CH₃, benzyl, and phenyl; R^(2c), at each occurrence, is selected from CF₃, OH, OCH₃, CH₃, benzyl, and phenyl; alternatively, R² and R^(2a) combine to form a 5 or 6 membered saturated, partially unsaturated, or unsaturated ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S; R³, at each occurrence, is selected from H, CH₃, CH₂CH₃, and phenyl; R^(3a), at each occurrence, is selected from H, CH₃, CH₂CH₃, and phenyl; R⁴, at each occurrence, is selected from OH, Cl, F, CH₃, CH₂CH₃, NR²R^(2a), CH₂NR²R^(2a), C(O)R^(2b), NR²C(O)R^(2b), C(O)NR²R^(2a), and CF₃; R^(4a), at each occurrence, is selected from OH, Cl, F, CH₃, CH₂CH₃, NR²R^(2a), CH₂NR²R^(2a), C(O)R^(2b), C(O)NR²R^(2a), SO₂NR²R^(2a), S(O)_(p)R⁵, CF₃, and 1-CF₃-tetrazol-2-yl; R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl substituted with 0-2 R⁶, and benzyl substituted with 1 R⁶; R⁶, at each occurrence, is selected from H, OH, OCH₃, Cl, F, CH₃, CN, NO₂, NR²R^(2a), CH₂NR²R^(2a), and SO₂NR²R^(2a); R⁷, at each occurrence, is selected from H and C₁₋₃ alkyl; R⁸, at each occurrence, is selected from H, CH₃, and benzyl; R⁹, at each occurrence, is selected from H, CH₃, and benzyl; and, t, at each occurrence, is selected from 0 and
 1. 14. A compound according to claim 13, wherein; D is selected from NR⁷R⁸ and CH₂NR⁷R⁸, provided that D is substituted ortho to ring M on E; R^(1a) is absent or is selected from H, CH₃, CH₂CH₃, Cl, F, CF₃, OCH₃, NR²R^(2a), S(O)_(p)R^(2b), C(O)NR²R^(2a), CH₂S(O)_(p)R^(2a), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2c), CH₂C(O)R^(2c), and SO₂NR²R^(2a); R^(1b) is absent or is selected from H, CH₃, CH₂CH₃, Cl, F, CF₃, OCH₃, NR²R^(2a), S(O)_(p)R^(2b), C(O)NR²R^(2a), CH₂S(O)_(p)R^(2b), CH₂NR²S(O)_(p)R^(2b), C(O)R^(2b), CH₂C(O)R^(2b), and SO₂NR²R^(2a); A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R⁴; phenyl, pyridyl, and pyrimidyl; B is selected from: Y and X—Y; X is selected from —C(O)— and O; Y is NR²R^(2a), provided that X—Y do not form a O—N bond; alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R^(4a); phenyl, piperazinyl, pyridyl, pyrimidyl, morpholinyl, pyrrolidinyl, imidazolyl, and 1,2,3-triazolyl; R², at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl; R^(2a), at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl; R^(2b), at each occurrence, is selected from CF₃, OCH₃, CH₃, benzyl, and phenyl; R^(2c), at each occurrence, is selected from CF₃, OH, OCH₃, CH₃, benzyl, and phenyl; alternatively, R² and R^(2a) combine to form a ring system selected from pyrrolidinyl, piperazinyl and morpholino; R⁴, at each occurrence, is selected from Cl, F, CH₃, NR²R^(2a), and CF₃; R^(4a), at each occurrence, is selected from Cl, F, CH₃, CH₂NR²R^(2a), SO₂NR²R^(2a), S(O)_(p)R⁵, and CF₃; R⁵, at each occurrence, is selected from CF₃ and CH₃; R⁷, at each occurrence, is selected from H, CH₃, and CH₂CH₃; and, R⁸, at each occurrence, is selected from H and CH₃.
 15. A compound according to claim 1, wherein the compound is selected from: 1-(2′-Aminomethylphenyl)-5-[[(2′-methylsulfonyl)-3-fluoro-[1,1′]-biphen-4-yl]aminocarbonyl]-tetrazole; 1-(2′-Aminomethylphenyl)-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]-tetrazole; 1-[2-(Aminomethyl)phenyl]-5-[(2-fluoro)-(2′-methylsulfonyl-[1,1′]-biphen-4-yl)aminocarbonyl]triazole; and pharmaceutically acceptable salts thereof.
 16. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 17. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof. 